RARE DISEASE
Disorder of fatty acid oxidation and ketogenesis
Disorder of fatty acid oxidation and ketogenesis
Disorder of fatty acid oxidation and ketogenesis
Drug discovery
2
drugs
With orphan designations
Overview
Disorders of fatty acid oxidation and ketogenesis are inborn errors disrupting mitochondrial β-oxidation or carnitine-mediated transport, impairing energy production from fats [1][2]. Affected individuals experience hypoketotic hypoglycemia during catabolic stress, with risks of hepatic dysfunction, cardiomyopathy, rhabdomyolysis, and neurocognitive impairment [2][8]. These autosomal recessive conditions require lifelong management focused on metabolic stability and energy substrate optimization [2][16].
Burden
Acute crises cause life-threatening hypoglycemia, hepatic encephalopathy, or cardiac arrest [1][19]. Chronic complications include developmental delay, retinopathy (LCHAD), and cardiomyopathy [16][19]. Despite newborn screening, recurrent hospitalizations and neurocognitive deficits persist in 30–40% of cases [3][8].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
197 drug discovery papers about Disorder of fatty acid oxidation and ketogenesis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
197 drug discovery papers about Disorder of fatty acid oxidation and ketogenesis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-24 | Progressive Weakness and Hypoglycemia in a Child With Selective Eating: A Nutritional Mimic of a Fatty Acid Oxidation Disorder.
Severe selective eating in children can lead to clinically important nutritional deficiencies. We report a 5-year-old boy with autism spectrum disorder who presented with progressive weakness and hypoglycemia mimicking a fatty acid oxidation disorder (FAOD). His diet had consisted almost exclusively of white rice, and he had developed clinically significant manifestations of folate and vitamin A deficiency before this presentation. After several months of progressive weakness, he developed a generalized seizure with severe hypoglycemia and blunted ketogenesis during an intercurrent infection. Laboratory testing showed low riboflavin, low free carnitine with an elevated acylcarnitine-to-free carnitine ratio, and mild C6-C10 acylcarnitine elevations. Nerve conduction studies suggested sensory-predominant axonal neuropathy. These findings resembled multiple acyl-CoA dehydrogenase deficiency, a FAOD. Riboflavin and levocarnitine supplementation was followed by recovery of independent walking, with no recurrence over 7 years. This case illustrates a nutritional mimic of FAODs and highlights the need for nutritional and metabolic evaluation in selectively eating children with progressive weakness or hypoglycemia.
2026-02-16 | The Keto–Inflammatory Network: From Systems Biology to Biological Code
The transition from energy sufficiency to deficiency triggers complex metabolic and immune adaptations that have traditionally been viewed through a reductionist pathological lens. During early lactation, coordinated mobilization of adipose tissue, muscle protein, and bone minerals supports milk synthesis, with ketogenesis specifically arising from hepatic oxidation of non–esterified fatty acids. This review introduces the Keto–Inflammatory Network (KIN), a novel framework positioning ketonemia as an evolutionarily conserved adaptive response rather than inherent metabolic dysfunction. The KIN integrates β–hydroxybutyrate (BHB) signaling with immune modulation, epigenetic regulation, circadian rhythms, and microbiota interactions. Through mechanisms including NLRP3 inflammasome inhibition, HDAC–mediated epigenetic modifications, and HCAR2 receptor activation, ketone bodies orchestrate anti–inflammatory responses while maintaining metabolic flexibility. Building upon important precedent work recognizing beneficial roles of ketones in ruminant metabolism, this review synthesizes recent advances in immunometabolism and systems biology into an integrated framework. The KIN encompasses calcium–ketone integration through the Calci–Keto–Inflammatory Code (CKIC), temporal regulation via the Ketoinflammatory Clock, and trans–kingdom signaling through microbiota interactions. In dairy cattle, this perspective reframes periparturient ketonemia as existing on a continuum from adaptive to pathological, with biological meaning determined by integrated metabolic–inflammatory patterns rather than absolute ketone concentrations. The CKIC paradigm, while requiring prospective validation, suggests novel therapeutic approaches leveraging ketone signaling for inflammatory diseases, autoimmune conditions, and metabolic disorders while challenging traditional threshold–based ketosis management strategies. This systems–level understanding opens new avenues for precision interventions that work with, rather than against, evolved adaptive mechanisms refined through millions of years of mammalian evolution. By distinguishing ketonemia (measurable ketone elevation) from pathological ketosis (dysregulated ketone accumulation), and by integrating evidence from both ruminant and monogastric models, this review provides a comprehensive framework for next–generation metabolic medicine.
2026-02-09 | Distinct effects of ketogenic and non-ketogenic weight-loss diets on hepatic steatosis and mitochondrial metabolism in MASLD.
Weight loss is the cornerstone of therapy for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the optimal dietary approach for reducing intrahepatic triglycerides (IHTG) and the mechanisms underlying steatosis resolution remain poorly defined. We investigated whether weight loss via a ketogenic diet (KD) compared with a non-ketogenic diet (ND) differentially affects IHTG content, hepatic mitochondrial metabolism, and the circulating metabolome. Individuals with varying IHTG content underwent short-term hypocaloric KD and ND in a crossover design. Before and after each diet, IHTG was quantified by proton magnetic resonance spectroscopy and liver stiffness by magnetic resonance elastography. We used state-of-the-art isotope tracer methodology to compare in vivo rates of hepatic mitochondrial tricarboxylic acid (TCA) cycle oxidation, endogenous glucose production, and β-hydroxybutyrate production (ketogenesis). Targeted plasma metabolomics by NMR and LC-MS was used to evaluate systemic metabolic responses. Despite similar energy deficits and body fat loss, IHTG decreased 45% more with KD than ND (-29% vs. -20%), accompanied by a threefold greater improvement in hepatic insulin sensitivity (59% vs. 21%). KD, but not ND, markedly reduced serum insulin concentrations (-54%), thereby promoting lipolysis and intrahepatic fatty acid partitioning toward mitochondrial β-oxidation, increasing hepatic mitochondrial [NADH]/[NAD+] (redox state) (+51%), and decreasing rates of hepatic mitochondrial TCA cycle oxidation (-34%). KD, but not ND, increased plasma concentrations of branched-chain amino acids, acylcarnitines, and TCA cycle intermediates. Both diets ameliorated MASLD, but KD produced a greater reduction in IHTG owing to a starvation-like metabolic state. However, the benefits of KD were accompanied by increased hepatic mitochondrial redox state and suppression of TCA cycle oxidation, which are features previously linked to progressive liver injury. This study provides mechanistic justification for considering dietary composition, in addition to caloric restriction, as a key determinant of steatosis resolution in metabolic dysfunction-associated steatotic liver disease (MASLD). The findings highlight a potential trade-off between greater short-term reductions in liver fat and the emergence of metabolic features previously associated with increased susceptibility to liver injury. While a ketogenic diet may facilitate rapid liver fat reduction in selected clinical contexts, its use should be approached cautiously, particularly in individuals with advanced MASLD. These results underscore the need for systematic evaluation of dietary composition as a determinant of both efficacy and safety of nutritional interventions for MASLD. NCT03737071.
2025-07-01 | The Multifaceted Influence of Beta-Hydroxybutyrate on Autophagy, Mitochondrial Metabolism, and Epigenetic Regulation.
Beta-hydroxybutyrate (BHB), a key ketone body produced during fatty acid metabolism, plays critical roles in various physiological and pathological conditions. Synthesized in the liver through ketogenesis, BHB serves as an essential energy substrate during glucose deprivation, supporting survival by efficiently utilizing fat reserves. It crosses the blood-brain barrier, providing energy for neuronal function, enhancing cognitive processes such as learning and memory, and offering neuroprotection by modulating synaptic plasticity and neurotransmitter levels. BHB's impact extends to cellular pathways, including autophagy, mitochondrial biogenesis, and epigenetic regulation. By modulating autophagy, BHB ensures mitochondrial integrity and function through intricate molecular pathways involving AMPK, mTOR, PINK1/Parkin, and others. This regulation plays vital roles in neurodegenerative diseases, metabolic disorders, cancer, and cardiovascular diseases, reducing oxidative stress and preventing cellular dysfunction. Epigenetically, BHB acts as an endogenous histone deacetylase inhibitor, inducing beneficial histone modifications that enhance cellular resilience and stress responses. This epigenetic influence is crucial in conditions like diabetes and cancer, aiding insulin secretion, protecting pancreatic beta cells, and impacting cancer cell gene expression and survival. Furthermore, BHB's therapeutic potential is evident in its ability to improve mitochondrial function across various tissues, including neurons, muscle, and liver. By enhancing mitochondrial respiration, reducing oxidative stress, and altering metabolic pathways, BHB mitigates conditions such as ICU-acquired weakness, nonalcoholic fatty liver disease, and cardiovascular diseases. BHB's modulation of autophagy and epigenetic regulation underscores its comprehensive role in cellular homeostasis and health across multiple physiological contexts, providing a foundation for future therapeutic strategies.
2024-11-21 | Identification of chikusetsusaponin IVa as a novel lysine-specific demethylase 1 inhibitor that ameliorates high fat diet-induced MASLD in mice.
Diet-induced metabolic dysfunction steatotic liver disease (MASLD) is also called as non-alcoholic fatty liver disease (NAFLD) with limited effective strategies available. We previously have shown that chikusetsusaponin IVa (CHS), a dietary saponin from herbs in South American known for their metabolic benefits, mitigates diet-induced diabetes. In this study we investigated the beneficial effects of CHS on MASLD and the underlying mechanisms. MAFLD mouse model was established by the high-fat diet (HFD) for 6 weeks and then were treated with CHS (50 mg·kg-1·d-1, i.g.) for another 8 weeks. By conducting transcriptomic analysis in palmitic acid-treated HepG2 cells and primary hepatocytes as well as lipidomic analysis in liver tissues, we demonstrated that HFD activated the intestinal farnesoid X receptor (FXR) pathway, leading to the release of FGF15/19, which in turn promoted hepatic FXR-SHP binding with cAMP-responsive element-binding protein H (CREBH), thereby inhibiting CREBH-mediated fatty acid oxidation (FAO) and ketogenesis. Intriguingly, we found that CHS improved lipid metabolism in HFD mice by suppressing the enterohepatic crosstalk of FXR-SHP to enhance CREBH transactivation. Among these, lysine-specific demethylase 1 (LSD1)-mediated histone demethylation played a crucial role in lipid metabolic reprogramming. Moreover, we identified LSD1 as a critical cellular target of CHS, directly binding to Lys661 and Tyr761 of LSD1 to inhibit its histone demethylation activity. Our results suggest that targeting intestinal LSD1 with CHS could be a promising strategy for MAFLD treatment, offering new insights into the bioavailability and efficacy of natural products.
proteins
2024-01-02 | Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease
Abstract Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.
2023-09-04 | Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients
Abstract Background Monogenetic inborn errors of metabolism cause a wide phenotypic heterogeneity that may even differ between family members carrying the same genetic variant. Computational modelling of metabolic networks may identify putative sources of this inter-patient heterogeneity. Here, we mainly focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inborn error of the mitochondrial fatty acid oxidation (mFAO). It is an enigma why some MCADD patients—if untreated—are at risk to develop severe metabolic decompensations, whereas others remain asymptomatic throughout life. We hypothesised that an ability to maintain an increased free mitochondrial CoA (CoASH) and pathway flux might distinguish asymptomatic from symptomatic patients. Results We built and experimentally validated, for the first time, a kinetic model of the human liver mFAO. Metabolites were partitioned according to their water solubility between the bulk aqueous matrix and the inner membrane. Enzymes are also either membrane-bound or in the matrix. This metabolite partitioning is a novel model attribute and improved predictions. MCADD substantially reduced pathway flux and CoASH, the latter due to the sequestration of CoA as medium-chain acyl-CoA esters. Analysis of urine from MCADD patients obtained during a metabolic decompensation showed an accumulation of medium- and short-chain acylcarnitines, just like the acyl-CoA pool in the MCADD model. The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. Proteome analysis of MCADD patient-derived fibroblasts indeed revealed elevated levels of SCAD in a patient with a clinically asymptomatic state. This is a rescue for MCADD that has not been explored before. Personalised models based on these proteomics data confirmed an increased pathway flux and CoASH in the model of an asymptomatic patient compared to those of symptomatic MCADD patients. Conclusions We present a detailed, validated kinetic model of mFAO in human liver, with solubility-dependent metabolite partitioning. Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. Further development of personalised metabolic models is a promising direction to improve individualised risk assessment, management and monitoring for inborn errors of metabolism.
2022-07-15 | Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis
Abstract Unrestrained ketogenesis leads to life-threatening ketoacidosis whose incidence is high in patients with diabetes. While insulin therapy reduces ketogenesis this approach is sub-optimal. Here, we report an insulin-independent pathway able to normalize diabetic ketogenesis. By generating insulin deficient male mice lacking or re-expressing Toll-Like Receptor 4 (TLR4) only in liver or hepatocytes, we demonstrate that hepatic TLR4 in non-parenchymal cells mediates the ketogenesis-suppressing action of S100A9. Mechanistically, S100A9 acts extracellularly to activate the mechanistic target of rapamycin complex 1 (mTORC1) in a TLR4-dependent manner. Accordingly, hepatic-restricted but not hepatocyte-restricted loss of Tuberous Sclerosis Complex 1 (TSC1, an mTORC1 inhibitor) corrects insulin-deficiency-induced hyperketonemia. Therapeutically, recombinant S100A9 administration restrains ketogenesis and improves hyperglycemia without causing hypoglycemia in diabetic mice. Also, circulating S100A9 in patients with ketoacidosis is only marginally increased hence unveiling a window of opportunity to pharmacologically augment S100A9 for preventing unrestrained ketogenesis. In summary, our findings reveal the hepatic S100A9-TLR4-mTORC1 axis in non-parenchymal cells as a promising therapeutic target for restraining diabetic ketogenesis.
2019-09-20 | Fibroblast growth factor-21 (FGF21) administration to early-lactating dairy cows. II. Pharmacokinetics, whole-animal performance, and lipid metabolism
Dairy cows cope with severe energy insufficiency in early lactation by engaging in intense and sustained mobilization of fatty acids from adipose tissue. An unwanted side effect of this adaptation is excessive lipid accumulation in the liver, which in turn impairs hepatic functions. Mice experiencing increased hepatic fatty acid flux are protected from this condition through coordinated actions of the newly described hormone fibroblast growth factor-21 (FGF21) on liver and adipose tissue. The possibility of an analogous role for FGF21 in dairy cows is suggested by its rapid increase in plasma levels around parturition followed by chronically elevated levels in the first few weeks of lactation. To test this hypothesis, dairy cows were randomly assigned on d 12.6 ± 2.2 (± standard error) of lactation to receive either an excipient (control; n=6) or recombinant human FGF21 (n = 7), first as an FGF21 bolus of 3 mg/kg of body weight (BW) followed 2 d later by a constant i.v. infusion of FGF21 at a rate of 6.3 mg/kg of metabolic BW for 9 consecutive days. After bolus administration, human FGF21 circulated with a half-life of 194 min, and its constant infusion increased total plasma concentration 117-fold over levels in excipient-infused cows. The FGF21 treatment had no effect on voluntary feed intake, milk yield, milk energy output, or net energy balance measured over the 9-d infusion or on final BW. Plasma fatty acids circulated at lower concentrations in the FGF21 group than in the control group for the 8-h period following bolus administration, but this reduction was not significant during the period of constant i.v. infusion. Treatment with FGF21 caused a 50% reduction in triglyceride content in liver biopsies taken at the end of the constant i.v. infusion without altering the mRNA abundance of key genes involved in the transport, acyl coenzyme A activation, or oxidation of fatty acids. In contrast, FGF21 treatment ablated the recovery of plasma insulin-like growth factor-1 seen in control cows during the 9-d i.v. infusion period despite a tendency for higher plasma growth hormone. This effect was associated with increased hepatic mRNA abundance of the intracellular inhibitor of growth hormone receptor trafficking, LEPROT. Overall, these data confirm the ability of FGF21 to reduce lipid accumulation in bovine liver and suggest the possibility that FGF21 does so by attenuating the hepatic influx of adipose tissue-derived fatty acids.
2019-04-01 | DEPP/DEPP1/C10ORF10 regulates hepatic glucose and fat metabolism partly via ROS-induced FGF21.
Decidual protein induced by progesterone (DEPP/DEPP1/C10ORF10) is induced by denying access to food and reduced by refeeding in insulin-sensitive organs in vivo. The negative regulation of DEPP by insulin is also proven in several cell lines. However, the functions of DEPP in insulin-sensitive organs remain unknown. In the present study, we investigated the impact of DEPP on hepatic energy metabolism and addressed the underlying mechanisms. The metabolic effects of DEPP were investigated in mice with adenovirus-mediated hepatic overexpression. Liver triglyceride (TG), glycogen, and serum metabolites were detected by biochemical assays. Energy homeostasis was measured by indirect calorimetry. Quantitative PCR was used to examine expression of genes involved in fatty acid oxidation, ketogenesis, lipogenesis, and gluconeogenesis. To evaluate the role of fibroblast growth factor 21 (FGF21) mediating the metabolic effects of DEPP, FGF21 antibody was administrated intraperitoneally to mice at 24 h after the delivery of adenovirus, and the metabolic alterations were examined. Reactive oxygen species (ROS) levels were measured by catalase activity assay, live cell fluorescence, or quantitative PCR. Effects of DEPP on the phenotype of db/db mice were also assessed. Acute hepatic overexpression of DEPP significantly reduced serum glucose and TG levels, dramatically elevated β-hydroxybutyrate levels, and improved glucose clearance. Compared with controls, DEPP overexpression reduced food intake, the energy expenditure rate, and the respiratory quotient. DEPP overexpression significantly increased fatty acid oxidation and ketogenesis but suppressed lipid synthesis and gluconeogenesis. Investigations of the underlying mechanisms revealed that DEPP regulates energy metabolism by inducing oxidative stress. With the impairment of the ROS scavenging system and promotion of ROS formation, DEPP overexpression leads to ROS accumulation. FGF21 is upregulated in response to oxidative stress and mediates the effects of DEPP on fatty acid oxidation, ketogenesis, and lipid synthesis but not gluconeogenesis, as evidenced by the fact that the FGF21 antibody dramatically suppressed a DEPP-induced increase of fatty acid oxidation and ketogenesis, reversed the reduction of lipid synthesis, but did not change the suppression of gluconeogenesis. Moreover, overexpression of DEPP in db/ db mice led to a marked reduction in body weight and serum glucose levels and significantly improved insulin sensitivity. Hepatic overexpression of DEPP in mice promotes fatty acid oxidation and ketogenesis and suppresses lipogenesis and gluconeogenesis, which is partly mediated by FGF21 induced by elevated cellular ROS levels.-Li, W., Ji, M., Lin, Y., Miao, Y., Chen, S., Li, H. DEPP/DEPP1/C10ORF10 regulates hepatic glucose and fat metabolism partly via ROS-induced FGF21.
gene therapies
2022-02-03 | Bdh1 overexpression ameliorates hepatic injury by activation of Nrf2 in a MAFLD mouse model
In 2020, a group of experts officially suggested metabolic dysfunction associated with fatty liver disease "MAFLD" as a more appropriate overarching term than NAFLD, indicating the key role of metabolism in fatty liver disease. Bdh1, as the rate-limiting enzyme of ketone metabolism, acts as an important metabolic regulator in liver. However, the role of Bdh1 in MAFLD is unclear. In this study, we used the transgenic db/db mice as a MAFLD mouse model and observed the downregulated expression of Bdh1 in fatty liver. In addition, expression of Bdh1 was also reduced by palmitic acid (PA) treatment in LO2 cells. Bdh1 knockdown led to ROS overproduction and ROS-induced inflammation and apoptosis in LO2 cells, while Bdh1 overexpression protected LO2 cells from lipotoxicity by inhibiting ROS overproduction. Mechanistically, Bdh1-mediated βOHB metabolism inhibits ROS overproduction by activation of Nrf2 through enhancement of metabolic flux composed of βOHB-AcAc-succinate-fumarate. Notably, adeno-associated virus (AAV)-mediated Bdh1 overexpression successfully reversed the hepatic function indexes, fibrosis, inflammation, and apoptosis in fatty livers from db/db mice. In conclusion, our study revealed a Bdh1-mediated molecular mechanism in pathogenesis of metabolic dysfunction related liver disease and identified Bdh1 as a novel potential therapeutic target for MAFLD.
2018-11-07 | ChREBP Reciprocally Regulates Liver and Plasma Triacylglycerol Levels in Different Manners
Carbohydrate response element-binding protein (ChREBP) has an important role in the carbohydrate-mediated regulation of hepatic de novo lipogenesis, but the mechanism for how it regulates plasma triacylglycerol (TAG) levels has not been established. This study aimed to clarify the role of ChREBP in regulation of plasma TAG levels. We analyzed the metabolic changes in mice infected with an adenovirus expressing ChREBP Δ196 (Ad-ChREBP). Compared with adenovirus harboring green fluorescent protein infected mice, Ad-ChREBP-infected mice had higher plasma free fatty acid levels and paradoxically lower plasma 3-hydroxybutyrate levels through decreased fatty acid oxidation, rather than ketogenesis. Consistent with their hepatomegaly and increased lipogenic gene expression, the liver TAG contents were much higher. Regarding lipid composition, C16:0 was much lower and C18:1n-9 was much higher, compatible with increased stearoyl CoA desaturase-1 and ELOVL fatty acid elongase 6 expression. Furthermore, Ad-ChREBP-infected mice had decreased plasma TAG and very low density lipoprotein (VLDL)-TAG levels, consistent with decreased Angiopoietin-like protein 3 (Angptl3) and increased fibroblast growth factor (Fgf21) mRNA and protein levels. Finally, Ad-ChREBP infection increased white adipose tissue Ucp1 mRNA levels with increased plasma Fgf21 levels. Because Fgf21 and Angptl3 are known to activate and suppress lipolysis in adipose tissues and oxidative tissues, ChREBP appears to regulate plasma TAG levels by modulating Fgf21 and Angptl3 levels. Thus, ChREBP overexpression led to dissociation of hepatic steatosis from hyperlipidemia.
2018-04-26 | Hepatic PPARα function is controlled by polyubiquitination and proteasome‐mediated degradation through the coordinated actions of PAQR3 and HUWE1
Peroxisome proliferator-activated receptor α (PPARα) is a key transcriptional factor that regulates hepatic lipid catabolism by stimulating fatty acid oxidation and ketogenesis in an adaptive response to nutrient starvation. However, how PPARα is regulated by posttranslational modification is poorly understood. In this study, we identified that progestin and adipoQ receptor 3 (PAQR3) promotes PPARα ubiquitination through the E3 ubiquitin ligase HUWE1, thereby negatively modulating PPARα functions both in vitro and in vivo. Adenovirus-mediated Paqr3 knockdown and liver-specific deletion of the Paqr3 gene reduced hepatic triglyceride levels while increasing fatty acid oxidation and ketogenesis upon fasting. PAQR3 deficiency enhanced the fasting-induced expression of PPARα target genes, including those involved in fatty acid oxidation and fibroblast growth factor 21, a key molecule that mediates the metabolism-modulating effects of PPARα. PAQR3 directly interacted with PPARα and increased the polyubiquitination and proteasome-mediated degradation of PPARα. Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARα polyubiquitination. Additionally, PAQR3 enhanced the interaction between HUWE1 and PPARα.Ubiquitination modification through the coordinated action of PAQR3 with HUWE1 plays a crucial role in regulating the activity of PPARα in response to starvation. (Hepatology 2018;68:289-303).
2015-09-30 | Coordinate Activation of Redox-Dependent ASK1/TGF-β Signaling by a Multiprotein Complex (MPK38, ASK1, SMADs, ZPR9, and TRX) Improves Glucose and Lipid Metabolism in Mice
To explore the molecular connections between redox-dependent apoptosis signal-regulating kinase 1 (ASK1) and transforming growth factor-β (TGF-β) signaling pathways and to examine the physiological processes in which coordinated regulation of these two signaling pathways plays a critical role.We provide evidence that the ASK1 and TGF-β signaling pathways are interconnected by a multiprotein complex harboring murine protein serine-threonine kinase 38 (MPK38), ASK1, Sma- and Mad-related proteins (SMADs), zinc-finger-like protein 9 (ZPR9), and thioredoxin (TRX) and demonstrate that the activation of either ASK1 or TGF-β activity is sufficient to activate both the redox-dependent ASK1 and TGF-β signaling pathways. Physiologically, the restoration of the downregulated activation levels of ASK1 and TGF-β signaling in genetically and diet-induced obese mice by adenoviral delivery of SMAD3 or ZPR9 results in the amelioration of adiposity, hyperglycemia, hyperlipidemia, and impaired ketogenesis.Our data suggest that the multiprotein complex linking ASK1 and TGF-β signaling pathways may be a potential target for redox-mediated metabolic complications.
2013-01-01 | The role of adipose tissue circadian clocks in metabolic maintenance
The day-night recursion generated by rotation of the Earth around its axis imposes 24 hour rhythm of light and temperature changes on all organisms. To cope with these changes and associated challenges biological species from bacteria to humans developed an adaptational timer – the biological clock. In mammals virtually all cells have a cell-autonomous oscillator consisting of clock genes arranged in transcriptional-translational feedback loops (TTLs). Body array of single-cell clocks is organized in a hierarchical system with the master pacemaker located in the hypothalamus and peripheral clocks found in different organs. This setup facilitates an effective anticipation and synchronization of the physiology to different daily events in order to improve survival. When devoid of any external time information the circadian system is able to generate sustained oscillations in behavioral and physiological processes with an endogenous period length of approximately 24 hours (hence “circa” = approximately and “dies” =day in Latin). In the first part of the thesis we investigate the circadian biology of the adipose tissue. Using tissue culture explants taken from transgenic mouse with a circadian luciferase reporter we show that adipose tissues from various depots of the body bare a self-sustained clock. We found that Atgl and Hsl genes involved in the lipid mobilization (lipolysis) exhibit diurnal variations in the expression which were abrogated in circadian mutant mice. Using cell-based gene reporter techniques and chromatin immunoprecipitation we convincingly demonstrate that Atgl and Hsl are direct transcriptional targets of the key clock proteins, BMAL1 and CLOCK. In turn this leads to circadian variation in lipolysis efficiency as estimated by glycerol excretion rates from fat pads of wild-type animals. Importantly, circadian changes of lipolysis rate were abolished in adipose tissue of Clock∆19 and Bmal1-/- mutants. As the result, free fatty acid (FFA) blood content of wild-type animals was rhythmic, unlike in Clock∆19 and Bmal1-/- mutants, which had generally low and flat level of FFAs in the blood. As physiological consequence, impaired lipolysis results in decreased availability of FFAs as energy substrate and blunted response to prolonged fasting. On the other hand, lipolysis deficiency triggers accumulation of triglycerides in lipid droplets of adipocytes and thus leads to adiposity and ultimately to obesity. In the second part we generated a circadian mutant mouse deleting Bmal1 gene in the adipose tissues using the Cre/loxP gene targeting technology. Fabp4-Cre Bmal1 fl/fl mice showed impaired expression of Atgl and Hsl, which led to reduction of lipolysis in the adipose tissues accompanied by lower FFA content in the blood. Consistently, Fabp4-Cre Bmal1 fl/fl mutants mostly utilized carbohydrates instead of FFAs during the resting phase. Using this conditional knockout model we show that circadian regulation of lipolysis by the adipose clock is also important for body weight control. Indeed, Fabp4-Cre Bmal1 fl/fl mice became heavier than wild-type controls kept on standard diet and developed morbid obesity when fed with high-fat diet. In summary, we found that the adipose tissue clock is responsible for the regulation of lipid mobilization and their usage as energy source. We conclude that the adipocyte clock is an integral part of the circadian system, which normal functioning is required for metabolic homeostasis.
small molecules
2026-07-24 | Progressive Weakness and Hypoglycemia in a Child With Selective Eating: A Nutritional Mimic of a Fatty Acid Oxidation Disorder.
Severe selective eating in children can lead to clinically important nutritional deficiencies. We report a 5-year-old boy with autism spectrum disorder who presented with progressive weakness and hypoglycemia mimicking a fatty acid oxidation disorder (FAOD). His diet had consisted almost exclusively of white rice, and he had developed clinically significant manifestations of folate and vitamin A deficiency before this presentation. After several months of progressive weakness, he developed a generalized seizure with severe hypoglycemia and blunted ketogenesis during an intercurrent infection. Laboratory testing showed low riboflavin, low free carnitine with an elevated acylcarnitine-to-free carnitine ratio, and mild C6-C10 acylcarnitine elevations. Nerve conduction studies suggested sensory-predominant axonal neuropathy. These findings resembled multiple acyl-CoA dehydrogenase deficiency, a FAOD. Riboflavin and levocarnitine supplementation was followed by recovery of independent walking, with no recurrence over 7 years. This case illustrates a nutritional mimic of FAODs and highlights the need for nutritional and metabolic evaluation in selectively eating children with progressive weakness or hypoglycemia.
2026-02-16 | The Keto–Inflammatory Network: From Systems Biology to Biological Code
The transition from energy sufficiency to deficiency triggers complex metabolic and immune adaptations that have traditionally been viewed through a reductionist pathological lens. During early lactation, coordinated mobilization of adipose tissue, muscle protein, and bone minerals supports milk synthesis, with ketogenesis specifically arising from hepatic oxidation of non–esterified fatty acids. This review introduces the Keto–Inflammatory Network (KIN), a novel framework positioning ketonemia as an evolutionarily conserved adaptive response rather than inherent metabolic dysfunction. The KIN integrates β–hydroxybutyrate (BHB) signaling with immune modulation, epigenetic regulation, circadian rhythms, and microbiota interactions. Through mechanisms including NLRP3 inflammasome inhibition, HDAC–mediated epigenetic modifications, and HCAR2 receptor activation, ketone bodies orchestrate anti–inflammatory responses while maintaining metabolic flexibility. Building upon important precedent work recognizing beneficial roles of ketones in ruminant metabolism, this review synthesizes recent advances in immunometabolism and systems biology into an integrated framework. The KIN encompasses calcium–ketone integration through the Calci–Keto–Inflammatory Code (CKIC), temporal regulation via the Ketoinflammatory Clock, and trans–kingdom signaling through microbiota interactions. In dairy cattle, this perspective reframes periparturient ketonemia as existing on a continuum from adaptive to pathological, with biological meaning determined by integrated metabolic–inflammatory patterns rather than absolute ketone concentrations. The CKIC paradigm, while requiring prospective validation, suggests novel therapeutic approaches leveraging ketone signaling for inflammatory diseases, autoimmune conditions, and metabolic disorders while challenging traditional threshold–based ketosis management strategies. This systems–level understanding opens new avenues for precision interventions that work with, rather than against, evolved adaptive mechanisms refined through millions of years of mammalian evolution. By distinguishing ketonemia (measurable ketone elevation) from pathological ketosis (dysregulated ketone accumulation), and by integrating evidence from both ruminant and monogastric models, this review provides a comprehensive framework for next–generation metabolic medicine.
2026-02-09 | Distinct effects of ketogenic and non-ketogenic weight-loss diets on hepatic steatosis and mitochondrial metabolism in MASLD.
Weight loss is the cornerstone of therapy for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the optimal dietary approach for reducing intrahepatic triglycerides (IHTG) and the mechanisms underlying steatosis resolution remain poorly defined. We investigated whether weight loss via a ketogenic diet (KD) compared with a non-ketogenic diet (ND) differentially affects IHTG content, hepatic mitochondrial metabolism, and the circulating metabolome. Individuals with varying IHTG content underwent short-term hypocaloric KD and ND in a crossover design. Before and after each diet, IHTG was quantified by proton magnetic resonance spectroscopy and liver stiffness by magnetic resonance elastography. We used state-of-the-art isotope tracer methodology to compare in vivo rates of hepatic mitochondrial tricarboxylic acid (TCA) cycle oxidation, endogenous glucose production, and β-hydroxybutyrate production (ketogenesis). Targeted plasma metabolomics by NMR and LC-MS was used to evaluate systemic metabolic responses. Despite similar energy deficits and body fat loss, IHTG decreased 45% more with KD than ND (-29% vs. -20%), accompanied by a threefold greater improvement in hepatic insulin sensitivity (59% vs. 21%). KD, but not ND, markedly reduced serum insulin concentrations (-54%), thereby promoting lipolysis and intrahepatic fatty acid partitioning toward mitochondrial β-oxidation, increasing hepatic mitochondrial [NADH]/[NAD+] (redox state) (+51%), and decreasing rates of hepatic mitochondrial TCA cycle oxidation (-34%). KD, but not ND, increased plasma concentrations of branched-chain amino acids, acylcarnitines, and TCA cycle intermediates. Both diets ameliorated MASLD, but KD produced a greater reduction in IHTG owing to a starvation-like metabolic state. However, the benefits of KD were accompanied by increased hepatic mitochondrial redox state and suppression of TCA cycle oxidation, which are features previously linked to progressive liver injury. This study provides mechanistic justification for considering dietary composition, in addition to caloric restriction, as a key determinant of steatosis resolution in metabolic dysfunction-associated steatotic liver disease (MASLD). The findings highlight a potential trade-off between greater short-term reductions in liver fat and the emergence of metabolic features previously associated with increased susceptibility to liver injury. While a ketogenic diet may facilitate rapid liver fat reduction in selected clinical contexts, its use should be approached cautiously, particularly in individuals with advanced MASLD. These results underscore the need for systematic evaluation of dietary composition as a determinant of both efficacy and safety of nutritional interventions for MASLD. NCT03737071.
2025-07-01 | The Multifaceted Influence of Beta-Hydroxybutyrate on Autophagy, Mitochondrial Metabolism, and Epigenetic Regulation.
Beta-hydroxybutyrate (BHB), a key ketone body produced during fatty acid metabolism, plays critical roles in various physiological and pathological conditions. Synthesized in the liver through ketogenesis, BHB serves as an essential energy substrate during glucose deprivation, supporting survival by efficiently utilizing fat reserves. It crosses the blood-brain barrier, providing energy for neuronal function, enhancing cognitive processes such as learning and memory, and offering neuroprotection by modulating synaptic plasticity and neurotransmitter levels. BHB's impact extends to cellular pathways, including autophagy, mitochondrial biogenesis, and epigenetic regulation. By modulating autophagy, BHB ensures mitochondrial integrity and function through intricate molecular pathways involving AMPK, mTOR, PINK1/Parkin, and others. This regulation plays vital roles in neurodegenerative diseases, metabolic disorders, cancer, and cardiovascular diseases, reducing oxidative stress and preventing cellular dysfunction. Epigenetically, BHB acts as an endogenous histone deacetylase inhibitor, inducing beneficial histone modifications that enhance cellular resilience and stress responses. This epigenetic influence is crucial in conditions like diabetes and cancer, aiding insulin secretion, protecting pancreatic beta cells, and impacting cancer cell gene expression and survival. Furthermore, BHB's therapeutic potential is evident in its ability to improve mitochondrial function across various tissues, including neurons, muscle, and liver. By enhancing mitochondrial respiration, reducing oxidative stress, and altering metabolic pathways, BHB mitigates conditions such as ICU-acquired weakness, nonalcoholic fatty liver disease, and cardiovascular diseases. BHB's modulation of autophagy and epigenetic regulation underscores its comprehensive role in cellular homeostasis and health across multiple physiological contexts, providing a foundation for future therapeutic strategies.
2024-11-21 | Identification of chikusetsusaponin IVa as a novel lysine-specific demethylase 1 inhibitor that ameliorates high fat diet-induced MASLD in mice.
Diet-induced metabolic dysfunction steatotic liver disease (MASLD) is also called as non-alcoholic fatty liver disease (NAFLD) with limited effective strategies available. We previously have shown that chikusetsusaponin IVa (CHS), a dietary saponin from herbs in South American known for their metabolic benefits, mitigates diet-induced diabetes. In this study we investigated the beneficial effects of CHS on MASLD and the underlying mechanisms. MAFLD mouse model was established by the high-fat diet (HFD) for 6 weeks and then were treated with CHS (50 mg·kg-1·d-1, i.g.) for another 8 weeks. By conducting transcriptomic analysis in palmitic acid-treated HepG2 cells and primary hepatocytes as well as lipidomic analysis in liver tissues, we demonstrated that HFD activated the intestinal farnesoid X receptor (FXR) pathway, leading to the release of FGF15/19, which in turn promoted hepatic FXR-SHP binding with cAMP-responsive element-binding protein H (CREBH), thereby inhibiting CREBH-mediated fatty acid oxidation (FAO) and ketogenesis. Intriguingly, we found that CHS improved lipid metabolism in HFD mice by suppressing the enterohepatic crosstalk of FXR-SHP to enhance CREBH transactivation. Among these, lysine-specific demethylase 1 (LSD1)-mediated histone demethylation played a crucial role in lipid metabolic reprogramming. Moreover, we identified LSD1 as a critical cellular target of CHS, directly binding to Lys661 and Tyr761 of LSD1 to inhibit its histone demethylation activity. Our results suggest that targeting intestinal LSD1 with CHS could be a promising strategy for MAFLD treatment, offering new insights into the bioavailability and efficacy of natural products.
proteins
2024-01-02 | Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease
Abstract Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.
2023-09-04 | Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients
Abstract Background Monogenetic inborn errors of metabolism cause a wide phenotypic heterogeneity that may even differ between family members carrying the same genetic variant. Computational modelling of metabolic networks may identify putative sources of this inter-patient heterogeneity. Here, we mainly focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inborn error of the mitochondrial fatty acid oxidation (mFAO). It is an enigma why some MCADD patients—if untreated—are at risk to develop severe metabolic decompensations, whereas others remain asymptomatic throughout life. We hypothesised that an ability to maintain an increased free mitochondrial CoA (CoASH) and pathway flux might distinguish asymptomatic from symptomatic patients. Results We built and experimentally validated, for the first time, a kinetic model of the human liver mFAO. Metabolites were partitioned according to their water solubility between the bulk aqueous matrix and the inner membrane. Enzymes are also either membrane-bound or in the matrix. This metabolite partitioning is a novel model attribute and improved predictions. MCADD substantially reduced pathway flux and CoASH, the latter due to the sequestration of CoA as medium-chain acyl-CoA esters. Analysis of urine from MCADD patients obtained during a metabolic decompensation showed an accumulation of medium- and short-chain acylcarnitines, just like the acyl-CoA pool in the MCADD model. The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. Proteome analysis of MCADD patient-derived fibroblasts indeed revealed elevated levels of SCAD in a patient with a clinically asymptomatic state. This is a rescue for MCADD that has not been explored before. Personalised models based on these proteomics data confirmed an increased pathway flux and CoASH in the model of an asymptomatic patient compared to those of symptomatic MCADD patients. Conclusions We present a detailed, validated kinetic model of mFAO in human liver, with solubility-dependent metabolite partitioning. Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. Further development of personalised metabolic models is a promising direction to improve individualised risk assessment, management and monitoring for inborn errors of metabolism.
2022-07-15 | Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis
Abstract Unrestrained ketogenesis leads to life-threatening ketoacidosis whose incidence is high in patients with diabetes. While insulin therapy reduces ketogenesis this approach is sub-optimal. Here, we report an insulin-independent pathway able to normalize diabetic ketogenesis. By generating insulin deficient male mice lacking or re-expressing Toll-Like Receptor 4 (TLR4) only in liver or hepatocytes, we demonstrate that hepatic TLR4 in non-parenchymal cells mediates the ketogenesis-suppressing action of S100A9. Mechanistically, S100A9 acts extracellularly to activate the mechanistic target of rapamycin complex 1 (mTORC1) in a TLR4-dependent manner. Accordingly, hepatic-restricted but not hepatocyte-restricted loss of Tuberous Sclerosis Complex 1 (TSC1, an mTORC1 inhibitor) corrects insulin-deficiency-induced hyperketonemia. Therapeutically, recombinant S100A9 administration restrains ketogenesis and improves hyperglycemia without causing hypoglycemia in diabetic mice. Also, circulating S100A9 in patients with ketoacidosis is only marginally increased hence unveiling a window of opportunity to pharmacologically augment S100A9 for preventing unrestrained ketogenesis. In summary, our findings reveal the hepatic S100A9-TLR4-mTORC1 axis in non-parenchymal cells as a promising therapeutic target for restraining diabetic ketogenesis.
2019-09-20 | Fibroblast growth factor-21 (FGF21) administration to early-lactating dairy cows. II. Pharmacokinetics, whole-animal performance, and lipid metabolism
Dairy cows cope with severe energy insufficiency in early lactation by engaging in intense and sustained mobilization of fatty acids from adipose tissue. An unwanted side effect of this adaptation is excessive lipid accumulation in the liver, which in turn impairs hepatic functions. Mice experiencing increased hepatic fatty acid flux are protected from this condition through coordinated actions of the newly described hormone fibroblast growth factor-21 (FGF21) on liver and adipose tissue. The possibility of an analogous role for FGF21 in dairy cows is suggested by its rapid increase in plasma levels around parturition followed by chronically elevated levels in the first few weeks of lactation. To test this hypothesis, dairy cows were randomly assigned on d 12.6 ± 2.2 (± standard error) of lactation to receive either an excipient (control; n=6) or recombinant human FGF21 (n = 7), first as an FGF21 bolus of 3 mg/kg of body weight (BW) followed 2 d later by a constant i.v. infusion of FGF21 at a rate of 6.3 mg/kg of metabolic BW for 9 consecutive days. After bolus administration, human FGF21 circulated with a half-life of 194 min, and its constant infusion increased total plasma concentration 117-fold over levels in excipient-infused cows. The FGF21 treatment had no effect on voluntary feed intake, milk yield, milk energy output, or net energy balance measured over the 9-d infusion or on final BW. Plasma fatty acids circulated at lower concentrations in the FGF21 group than in the control group for the 8-h period following bolus administration, but this reduction was not significant during the period of constant i.v. infusion. Treatment with FGF21 caused a 50% reduction in triglyceride content in liver biopsies taken at the end of the constant i.v. infusion without altering the mRNA abundance of key genes involved in the transport, acyl coenzyme A activation, or oxidation of fatty acids. In contrast, FGF21 treatment ablated the recovery of plasma insulin-like growth factor-1 seen in control cows during the 9-d i.v. infusion period despite a tendency for higher plasma growth hormone. This effect was associated with increased hepatic mRNA abundance of the intracellular inhibitor of growth hormone receptor trafficking, LEPROT. Overall, these data confirm the ability of FGF21 to reduce lipid accumulation in bovine liver and suggest the possibility that FGF21 does so by attenuating the hepatic influx of adipose tissue-derived fatty acids.
2019-04-01 | DEPP/DEPP1/C10ORF10 regulates hepatic glucose and fat metabolism partly via ROS-induced FGF21.
Decidual protein induced by progesterone (DEPP/DEPP1/C10ORF10) is induced by denying access to food and reduced by refeeding in insulin-sensitive organs in vivo. The negative regulation of DEPP by insulin is also proven in several cell lines. However, the functions of DEPP in insulin-sensitive organs remain unknown. In the present study, we investigated the impact of DEPP on hepatic energy metabolism and addressed the underlying mechanisms. The metabolic effects of DEPP were investigated in mice with adenovirus-mediated hepatic overexpression. Liver triglyceride (TG), glycogen, and serum metabolites were detected by biochemical assays. Energy homeostasis was measured by indirect calorimetry. Quantitative PCR was used to examine expression of genes involved in fatty acid oxidation, ketogenesis, lipogenesis, and gluconeogenesis. To evaluate the role of fibroblast growth factor 21 (FGF21) mediating the metabolic effects of DEPP, FGF21 antibody was administrated intraperitoneally to mice at 24 h after the delivery of adenovirus, and the metabolic alterations were examined. Reactive oxygen species (ROS) levels were measured by catalase activity assay, live cell fluorescence, or quantitative PCR. Effects of DEPP on the phenotype of db/db mice were also assessed. Acute hepatic overexpression of DEPP significantly reduced serum glucose and TG levels, dramatically elevated β-hydroxybutyrate levels, and improved glucose clearance. Compared with controls, DEPP overexpression reduced food intake, the energy expenditure rate, and the respiratory quotient. DEPP overexpression significantly increased fatty acid oxidation and ketogenesis but suppressed lipid synthesis and gluconeogenesis. Investigations of the underlying mechanisms revealed that DEPP regulates energy metabolism by inducing oxidative stress. With the impairment of the ROS scavenging system and promotion of ROS formation, DEPP overexpression leads to ROS accumulation. FGF21 is upregulated in response to oxidative stress and mediates the effects of DEPP on fatty acid oxidation, ketogenesis, and lipid synthesis but not gluconeogenesis, as evidenced by the fact that the FGF21 antibody dramatically suppressed a DEPP-induced increase of fatty acid oxidation and ketogenesis, reversed the reduction of lipid synthesis, but did not change the suppression of gluconeogenesis. Moreover, overexpression of DEPP in db/ db mice led to a marked reduction in body weight and serum glucose levels and significantly improved insulin sensitivity. Hepatic overexpression of DEPP in mice promotes fatty acid oxidation and ketogenesis and suppresses lipogenesis and gluconeogenesis, which is partly mediated by FGF21 induced by elevated cellular ROS levels.-Li, W., Ji, M., Lin, Y., Miao, Y., Chen, S., Li, H. DEPP/DEPP1/C10ORF10 regulates hepatic glucose and fat metabolism partly via ROS-induced FGF21.
gene therapies
2022-02-03 | Bdh1 overexpression ameliorates hepatic injury by activation of Nrf2 in a MAFLD mouse model
In 2020, a group of experts officially suggested metabolic dysfunction associated with fatty liver disease "MAFLD" as a more appropriate overarching term than NAFLD, indicating the key role of metabolism in fatty liver disease. Bdh1, as the rate-limiting enzyme of ketone metabolism, acts as an important metabolic regulator in liver. However, the role of Bdh1 in MAFLD is unclear. In this study, we used the transgenic db/db mice as a MAFLD mouse model and observed the downregulated expression of Bdh1 in fatty liver. In addition, expression of Bdh1 was also reduced by palmitic acid (PA) treatment in LO2 cells. Bdh1 knockdown led to ROS overproduction and ROS-induced inflammation and apoptosis in LO2 cells, while Bdh1 overexpression protected LO2 cells from lipotoxicity by inhibiting ROS overproduction. Mechanistically, Bdh1-mediated βOHB metabolism inhibits ROS overproduction by activation of Nrf2 through enhancement of metabolic flux composed of βOHB-AcAc-succinate-fumarate. Notably, adeno-associated virus (AAV)-mediated Bdh1 overexpression successfully reversed the hepatic function indexes, fibrosis, inflammation, and apoptosis in fatty livers from db/db mice. In conclusion, our study revealed a Bdh1-mediated molecular mechanism in pathogenesis of metabolic dysfunction related liver disease and identified Bdh1 as a novel potential therapeutic target for MAFLD.
2018-11-07 | ChREBP Reciprocally Regulates Liver and Plasma Triacylglycerol Levels in Different Manners
Carbohydrate response element-binding protein (ChREBP) has an important role in the carbohydrate-mediated regulation of hepatic de novo lipogenesis, but the mechanism for how it regulates plasma triacylglycerol (TAG) levels has not been established. This study aimed to clarify the role of ChREBP in regulation of plasma TAG levels. We analyzed the metabolic changes in mice infected with an adenovirus expressing ChREBP Δ196 (Ad-ChREBP). Compared with adenovirus harboring green fluorescent protein infected mice, Ad-ChREBP-infected mice had higher plasma free fatty acid levels and paradoxically lower plasma 3-hydroxybutyrate levels through decreased fatty acid oxidation, rather than ketogenesis. Consistent with their hepatomegaly and increased lipogenic gene expression, the liver TAG contents were much higher. Regarding lipid composition, C16:0 was much lower and C18:1n-9 was much higher, compatible with increased stearoyl CoA desaturase-1 and ELOVL fatty acid elongase 6 expression. Furthermore, Ad-ChREBP-infected mice had decreased plasma TAG and very low density lipoprotein (VLDL)-TAG levels, consistent with decreased Angiopoietin-like protein 3 (Angptl3) and increased fibroblast growth factor (Fgf21) mRNA and protein levels. Finally, Ad-ChREBP infection increased white adipose tissue Ucp1 mRNA levels with increased plasma Fgf21 levels. Because Fgf21 and Angptl3 are known to activate and suppress lipolysis in adipose tissues and oxidative tissues, ChREBP appears to regulate plasma TAG levels by modulating Fgf21 and Angptl3 levels. Thus, ChREBP overexpression led to dissociation of hepatic steatosis from hyperlipidemia.
2018-04-26 | Hepatic PPARα function is controlled by polyubiquitination and proteasome‐mediated degradation through the coordinated actions of PAQR3 and HUWE1
Peroxisome proliferator-activated receptor α (PPARα) is a key transcriptional factor that regulates hepatic lipid catabolism by stimulating fatty acid oxidation and ketogenesis in an adaptive response to nutrient starvation. However, how PPARα is regulated by posttranslational modification is poorly understood. In this study, we identified that progestin and adipoQ receptor 3 (PAQR3) promotes PPARα ubiquitination through the E3 ubiquitin ligase HUWE1, thereby negatively modulating PPARα functions both in vitro and in vivo. Adenovirus-mediated Paqr3 knockdown and liver-specific deletion of the Paqr3 gene reduced hepatic triglyceride levels while increasing fatty acid oxidation and ketogenesis upon fasting. PAQR3 deficiency enhanced the fasting-induced expression of PPARα target genes, including those involved in fatty acid oxidation and fibroblast growth factor 21, a key molecule that mediates the metabolism-modulating effects of PPARα. PAQR3 directly interacted with PPARα and increased the polyubiquitination and proteasome-mediated degradation of PPARα. Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARα polyubiquitination. Additionally, PAQR3 enhanced the interaction between HUWE1 and PPARα.Ubiquitination modification through the coordinated action of PAQR3 with HUWE1 plays a crucial role in regulating the activity of PPARα in response to starvation. (Hepatology 2018;68:289-303).
2015-09-30 | Coordinate Activation of Redox-Dependent ASK1/TGF-β Signaling by a Multiprotein Complex (MPK38, ASK1, SMADs, ZPR9, and TRX) Improves Glucose and Lipid Metabolism in Mice
To explore the molecular connections between redox-dependent apoptosis signal-regulating kinase 1 (ASK1) and transforming growth factor-β (TGF-β) signaling pathways and to examine the physiological processes in which coordinated regulation of these two signaling pathways plays a critical role.We provide evidence that the ASK1 and TGF-β signaling pathways are interconnected by a multiprotein complex harboring murine protein serine-threonine kinase 38 (MPK38), ASK1, Sma- and Mad-related proteins (SMADs), zinc-finger-like protein 9 (ZPR9), and thioredoxin (TRX) and demonstrate that the activation of either ASK1 or TGF-β activity is sufficient to activate both the redox-dependent ASK1 and TGF-β signaling pathways. Physiologically, the restoration of the downregulated activation levels of ASK1 and TGF-β signaling in genetically and diet-induced obese mice by adenoviral delivery of SMAD3 or ZPR9 results in the amelioration of adiposity, hyperglycemia, hyperlipidemia, and impaired ketogenesis.Our data suggest that the multiprotein complex linking ASK1 and TGF-β signaling pathways may be a potential target for redox-mediated metabolic complications.
2013-01-01 | The role of adipose tissue circadian clocks in metabolic maintenance
The day-night recursion generated by rotation of the Earth around its axis imposes 24 hour rhythm of light and temperature changes on all organisms. To cope with these changes and associated challenges biological species from bacteria to humans developed an adaptational timer – the biological clock. In mammals virtually all cells have a cell-autonomous oscillator consisting of clock genes arranged in transcriptional-translational feedback loops (TTLs). Body array of single-cell clocks is organized in a hierarchical system with the master pacemaker located in the hypothalamus and peripheral clocks found in different organs. This setup facilitates an effective anticipation and synchronization of the physiology to different daily events in order to improve survival. When devoid of any external time information the circadian system is able to generate sustained oscillations in behavioral and physiological processes with an endogenous period length of approximately 24 hours (hence “circa” = approximately and “dies” =day in Latin). In the first part of the thesis we investigate the circadian biology of the adipose tissue. Using tissue culture explants taken from transgenic mouse with a circadian luciferase reporter we show that adipose tissues from various depots of the body bare a self-sustained clock. We found that Atgl and Hsl genes involved in the lipid mobilization (lipolysis) exhibit diurnal variations in the expression which were abrogated in circadian mutant mice. Using cell-based gene reporter techniques and chromatin immunoprecipitation we convincingly demonstrate that Atgl and Hsl are direct transcriptional targets of the key clock proteins, BMAL1 and CLOCK. In turn this leads to circadian variation in lipolysis efficiency as estimated by glycerol excretion rates from fat pads of wild-type animals. Importantly, circadian changes of lipolysis rate were abolished in adipose tissue of Clock∆19 and Bmal1-/- mutants. As the result, free fatty acid (FFA) blood content of wild-type animals was rhythmic, unlike in Clock∆19 and Bmal1-/- mutants, which had generally low and flat level of FFAs in the blood. As physiological consequence, impaired lipolysis results in decreased availability of FFAs as energy substrate and blunted response to prolonged fasting. On the other hand, lipolysis deficiency triggers accumulation of triglycerides in lipid droplets of adipocytes and thus leads to adiposity and ultimately to obesity. In the second part we generated a circadian mutant mouse deleting Bmal1 gene in the adipose tissues using the Cre/loxP gene targeting technology. Fabp4-Cre Bmal1 fl/fl mice showed impaired expression of Atgl and Hsl, which led to reduction of lipolysis in the adipose tissues accompanied by lower FFA content in the blood. Consistently, Fabp4-Cre Bmal1 fl/fl mutants mostly utilized carbohydrates instead of FFAs during the resting phase. Using this conditional knockout model we show that circadian regulation of lipolysis by the adipose clock is also important for body weight control. Indeed, Fabp4-Cre Bmal1 fl/fl mice became heavier than wild-type controls kept on standard diet and developed morbid obesity when fed with high-fat diet. In summary, we found that the adipose tissue clock is responsible for the regulation of lipid mobilization and their usage as energy source. We conclude that the adipocyte clock is an integral part of the circadian system, which normal functioning is required for metabolic homeostasis.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Disorder of fatty acid oxidation and ketogenesis, including 1 approved therapy.
2 orphan drug designations for Disorder of fatty acid oxidation and ketogenesis, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Sodium (4-{(E)-3-(4-fluorophenyl)-3-[4-(3-morpholin-4-yl-prop-1ynyl)phenyl]allyloxy}-2-methylphenoxy)acetate | small molecules | FDA | 2019-07-22 | — | Reneo Pharma Ltd |
triheptanoin [Dojolvi] | small molecules | FDA | 2015-04-15 | 2020-06-30 | Ultragenyx Pharmaceutical, Inc. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.