RARE DISEASE
Carnitine palmitoyl transferase 1A deficiency
Carnitine palmitoyl transferase 1A deficiency
Carnitine palmitoyl transferase 1A deficiency
Synonyms: CPT1A deficiency, Carnitine palmitoyl transferase IA deficiency, Hepatic carnitine palmitoyl transferase 1 deficiency, Hepatic carnitine palmitoyl transferase I deficiency, L-CPT1 deficiency, L-CPTI deficiency
Synonyms: CPT1A deficiency, Carnitine palmitoyl transferase IA deficiency, Hepatic carnitine palmitoyl transferase 1 deficiency, Hepatic carnitine palmitoyl transferase I deficiency, L-CPT1 deficiency, L-CPTI deficiency
Synonyms: CPT1A deficiency, Carnitine palmitoyl transferase IA deficiency, Hepatic carnitine palmitoyl transferase 1 deficiency, Hepatic carnitine palmitoyl transferase I deficiency, L-CPT1 deficiency, L-CPTI deficiency
Drug discovery
1
drug
With orphan designation
Overview
Carnitine palmitoyltransferase 1A (CPT1A) deficiency is an autosomal recessive disorder impairing mitochondrial long-chain fatty acid oxidation due to CPT1A gene mutations. It presents with fasting-induced hypoketotic hypoglycemia, hepatomegaly, hyperammonemia, and risk of hepatic encephalopathy or failure. Diagnosis combines biochemical findings (elevated free carnitine, low ketones) with genetic testing. Management centers on dietary strategies to prevent metabolic crises [1][2][7].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
119 drug discovery papers about Carnitine palmitoyl transferase 1A deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
119 drug discovery papers about Carnitine palmitoyl transferase 1A deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-04-13 | UFL1 deficiency disrupts skeletal muscle lipid metabolism by promoting the ACC1-FASN axis.
Skeletal muscle lipid metabolic homeostasis is essential for normal function and physical performance. Ubiquitin-fold modifier 1 ligase 1 (UFL1), the sole E3 ligase in the UFMylation system, is widely involved in lipid metabolism across various cell types, yet its specific role in skeletal muscle remains unclear. Using skeletal muscle-specific UFL1 knockout mice and UFL1-manipulated C2C12 cells, we found that UFL1 deficiency led to marked lipid droplet accumulation, elevated triglyceride (TG) and total cholesterol (TCH) levels, and upregulation of the lipid droplet coat protein perilipin 2 (PLIN2), whereas UFL1 overexpression reversed these effects. Mechanistically, expression of the lipogenic enzymes acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN) was significantly increased in UFL1-deficient tissues and cells, whereas protein levels of peroxisome proliferator-activated receptor alpha (PPARα) and its downstream target carnitine palmitoyltransferase 1A (CPT1A) remained unchanged, effects reversed by UFL1 overexpression. Collectively, these findings establish UFL1 as a critical regulator of skeletal muscle lipid homeostasis through the ACC1-FASN axis, independent of fatty acid oxidation, revealing a novel target for treating skeletal muscle lipid metabolic dysfunction.
2026-04-02 | Cardiolipin alleviates insulin resistance by ameliorating mitochondrial dysfunction and promoting fatty acid oxidation.
Cardiolipin deficiency is closely associated with mitochondrial dysfunction and metabolic disorders, yet whether it directly modulates insulin resistance remains unknown. Here, we examined the effects of cardiolipin supplementation on insulin resistance and the underlying mechanisms using male C57BL/6J mice fed a high-fat diet, male db/db mice, and dexamethasone-induced insulin-resistant HepG2 cells, a well-established model for investigating hepatic insulin signaling. Intragastric administration of cardiolipin at 5 mg/kg lowered blood glucose, reduced weight gain, improved insulin sensitivity, and alleviated hepatic lipid accumulation in mice, along with decreased serum interleukin-6 and low-density lipoprotein cholesterol levels. Cardiolipin reduced the LC3-II/LC3-I ratio and Tom20 expression in both liver tissue and insulin-resistant HepG2 cells, indicative of enhanced mitophagy. In HepG2 cells, it also attenuated mitochondrial fragmentation, improved mitochondrial membrane potential, lowered reactive oxygen species production, and upregulated the expression of CPT1A and ACAD1. These findings demonstrate that cardiolipin mitigates hepatic insulin resistance by enhancing mitophagy and fatty acid oxidation, representing a promising therapeutic approach for insulin resistance-related metabolic disorders.
2026-03-14 | Betulinic Acid Attenuates Vascular Smooth Muscle Cell Senescence and Aortic Vascular Aging via PPAR-α/CPT1A-Mediated Fatty Acid Oxidation.
Vascular stiffness and aging are critical contributors to cardiovascular diseases. Whether betulinic acid (BA), a natural triterpenoid, alleviates vascular aging remains unclear. Mouse aortic smooth muscle cells (MASMCs) with oleic acid (OA)-induced lipotoxic senescence were treated with BA (30 μM). Transcriptomic analysis and functional assays were conducted. In vivo, ApoE-/- mice fed a high-fat diet received oral BA (25 mg/kg/day) for 14 weeks. OA-induced lipotoxic senescence was associated with overactivation of peroxisome proliferator-activated receptor alpha (PPAR-α)/fatty acid oxidation (FAO) signaling, which was attenuated by BA intervention. Molecular docking suggested that BA binds to the Arg226 site of PPAR-α, which was further supported by surface plasmon resonance analysis. BA significantly reduced OA-induced expression of P16, P21, and P53 (p < 0.05), inhibited reactive oxygen species generation, and improved mitochondrial function, indicating pronounced antisenescence effects of BA. Moreover, PPAR-α overexpression reversed these protective effects. In ApoE-/- mice, BA intervention reduced vascular pulse wave velocity (2.7 ± 0.32 vs. 3.3 ± 0.45 m/s, p < 0.05) and intima-media thickness (0.114 ± 0.012 vs. 0.137 ± 0.018 mm, p < 0.05). BA attenuates MASMC lipotoxic senescence and aortic metabolism-associated vascular aging by inhibiting PPAR-α/carnitine palmitoyl transferase 1A-mediated FAO, suggesting a potential metabolic-targeted strategy for preventing lipid-associated vascular aging.
2026-02-16 | Rubimaillin ameliorates liver fibrosis by triggering the ferroptosis of activated hepatic stellate cells through targeting CPT1A.
Liver fibrosis is defined as the excessive accumulation of extracellular matrix proteins in the liver due to chronic liver injury. Targeted ferroptosis of activated hepatic stellate cells (HSCs) is considered a promising therapeutic strategy for liver fibrosis. Rubimaillin (Rub), a naphthoquinone compound extracted from traditional Chinese medicine Rubia cordifolia L., exhibits various activities in multiple diseases. This study aimed to investigate the anti-hepatic fibrosis effect, the direct protein target, and molecular mechanism of Rub. Here, our results demonstrated that Rub effectively ameliorated liver fibrosis via triggering the ferroptosis of activated HSCs in mice models. Subsequently, we confirmed that Rub directly binds to carnitine palmitoyltransferase 1A (CPT1A) at SER592, THR594, and THR689, and inhibits its activity using PROTAC technology, computer molecular dynamics simulations, CETSA, DARTS, BLI, and site mutation assays. Further, the inhibition or deficiency of CPT1A in activated HSCs could trigger metabolic reprogramming-mediated ferroptosis. Moreover, CPT1A deficiency or overexpression could eliminate the effects of Rub-induced ferroptosis. Mechanistically, Rub-induced ferroptosis in activated HSCs was associated with metabolic reprogramming mediated by targeting CPT1A. Taken together, our results indicate the beneficial effects, the direct protein target and the molecular mechanism via which Rub induces ferroptosis in activated HSCs to ameliorate liver fibrosis.
2026-01-15 | Brown adipocyte-derived SAA3-CPT1A axis regulates diet-induced thermogenesis and protects against obesity.
Diet-induced thermogenesis (DIT), a critical component of energy expenditure driven by brown adipose tissue (BAT), is essential for maintaining metabolic health; however, its precise molecular regulation remains poorly understood. We investigated whether serum amyloid A3 (SAA3), a factor secreted by brown adipocytes, regulates DIT and protects against diet-induced obesity. Using two distinct mouse models: mice with brown adipocyte-specific Saa3 deletion and mice with lentiviral-mediated Saa3 overexpression in BAT, we examined energy expenditure, substrate utilization, and thermogenic responses under chow or short-term high-fat diet feeding. SAA3 expression in BAT was acutely induced by refeeding. Loss of SAA3 severely diminished postprandial DIT and total energy expenditure, leading to accelerated weight gain on a high-fat diet. Mechanistically, Saa3 deletion compromised uncoupling protein‑1 induction, chiefly by impairing adipose triglyceride lipase-driven lipolysis and, critically, by inhibiting carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation (FAO). Conversely, SAA3 overexpression robustly enhanced DIT, stimulated lipolysis and FAO, and promoted mitochondrial oxidative phosphorylation. Studies in primary brown adipocytes confirmed that SAA3 deficiency reduced CPT1A expression, palmitate-stimulated lipolysis, and mitochondrial respiration. Together, these findings identify the SAA3-CPT1A axis as a novel, BAT-intrinsic mechanism that couples nutrient sensing to uncoupling protein‑11 function via enhanced FAO. By promoting lipid utilization and postprandial energy dissipation, SAA3 optimizes postprandial thermogenesis and defends against obesity, highlighting conserved SAA signaling as a potential nutritional and therapeutic target in metabolic disease.
gene therapies
2025-06-12 | Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers ApoB-Containing Lipoproteins in Mice.
Genome- and epigenome-wide association studies have associated variants and methylation status of CPT1a (carnitine palmitoyltransferase 1a) to reductions in VLDL (very low-density lipoprotein) cholesterol and triglyceride levels. The objective of this study was to determine the mechanisms by which CPT1a-dependent mitochondrial fatty acid oxidation influences hepatic and lipoprotein metabolism. Eight-week-old male and female Cpt1a-floxed mice (Cpt1afl/fl) and Cpt1a-floxed mice expressing the human apo B100 transgene (Cpt1afl/fl/B100Tg) were administered control adeno-associated virus or adeno-associated virus encoding Cre-recombinase under control of a liver-specific promoter (TBG-Cre [thyroxin-binding globulin]). Control and liver-specific knockout mice were placed on a low-fat control or western-type diet (42% kcal fat, 0.2% cholesterol) for 16 weeks. Livers were collected and used for histological and lipid analysis, while gene and protein expression were measured by bulk RNA-sequencing and immunoblotting, respectively. Lipoprotein composition in plasma was determined by size exclusion chromatography and nuclear magnetic resonance. Rates of VLDL-triglyceride secretion were quantified after lipase inhibition with poloxamer 407. Liquid and gas chromatography-mass spectrometry were used to measure bile acid species and fecal neutral sterols, respectively. We report significant associations between the presence of CPT1a SNPs (single nucleotide polymorphisms) and reductions in plasma cholesterol, as well as positive associations between hepatic Cpt1a expression and plasma cholesterol levels across inbred mouse strains. Mechanistic studies show that both wild-type and human apo B100 (apoB)-transgenic mice with liver-specific deletion of Cpt1a (liver-specific knockout) display lower circulating apoB levels consistent with reduced LDL (low-density lipoprotein)-cholesterol and LDL particle number. Despite a reduction in steady-state plasma lipids, VLDL-triglyceride and VLDL cholesterol secretion rates are increased, suggesting accelerated clearance of apoB-LPs (apoB-containing lipoproteins) in liver-specific knockout mice. Mechanistic approaches show greater PPARα (peroxisome proliferator-activated receptor α) signaling which favors enhanced lipoprotein lipase-mediated metabolism of apoB-LPs, including increases in apo AIV and apo CII and reductions in apo CIII and Angptl3 (angiopoietin-like 3). These studies provide mechanistic insight linking genetic variants and methylation status of CPT1a to reductions in circulating apoB-LPs in humans.
2025-01-07 | Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers Apolipoprotein B Containing Lipoproteins in Mice.
Genome- and epigenome-wide association studies have associated variants and methylation status of carnitine palmitoyltransferase 1a (CPT1a) to reductions in very low-density lipoprotein (VLDL) cholesterol and triglyceride levels. We report significant associations between the presence of CPT1a SNPs and reductions in plasma cholesterol, as well as positive associations between hepatic Cpt1a expression and plasma cholesterol levels across inbred mouse strains. Mechanistic studies show that both wild type and human apolipoprotein B100 (apoB)-transgenic mice with liver-specific deletion of Cpt1a (LKO) display lower circulating apoB levels consistent with reduced LDL-cholesterol (LDL-C) and LDL particle number. Despite a reduction in steady-state plasma lipids, VLDL-triglyceride (VLDL-TG) and cholesterol (VLDL-C) secretion rates are increased, suggesting accelerated clearance of apoB-containing lipoproteins (apoB-LPs) in LKO mice. Mechanistic approaches show greater peroxisome proliferator activated receptor α (PPARα) signaling which favors enhanced lipoprotein lipase-mediated metabolism of apoB-LPs, including increases in ApoCII and ApoAIV and reductions in ApoCIII & Angptl3. These studies provide mechanistic insight linking genetic variants and methylation status of CPT1a to reductions in circulating apoB-LPs in humans. Loss-of-function SNPs in CPT1a associate with reductions in plasma cholesterol in humans Hepatic Cpt1a expression positively associates with plasma cholesterol levels across inbred strains of miceLiver-specific Cpt1a deficiency lowers circulating apoB, plasma cholesterol, LDL-C, and LDL particle numberCpt1a ablation activates PPARα and favors clearance of apoB-containing lipoproteins.
2016-08-09 | Muscle expression of a malonyl-CoA-insensitive carnitine palmitoyltransferase-1 protects mice against high-fat/high-sucrose diet-induced insulin resistance
Impaired skeletal muscle mitochondrial fatty acid oxidation (mFAO) has been implicated in the etiology of insulin resistance. Carnitine palmitoyltransferase-1 (CPT1) is a key regulatory enzyme of mFAO whose activity is inhibited by malonyl-CoA, a lipogenic intermediate. Whereas increasing CPT1 activity in vitro has been shown to exert a protective effect against lipid-induced insulin resistance in skeletal muscle cells, only a few studies have addressed this issue in vivo. We thus examined whether a direct modulation of muscle CPT1/malonyl-CoA partnership is detrimental or beneficial for insulin sensitivity in the context of diet-induced obesity. By using a Cre- LoxP recombination approach, we generated mice with skeletal muscle-specific and inducible expression of a mutated CPT1 form (CPT1mt) that is active but insensitive to malonyl-CoA inhibition. When fed control chow, homozygous CPT1mt transgenic (dbTg) mice exhibited decreased CPT1 sensitivity to malonyl-CoA inhibition in isolated muscle mitochondria, which was sufficient to substantially increase ex vivo muscle mFAO capacity and whole body fatty acid utilization in vivo. Moreover, dbTg mice were less prone to high-fat/high-sucrose (HFHS) diet-induced insulin resistance and muscle lipotoxicity despite similar body weight gain, adiposity, and muscle malonyl-CoA content. Interestingly, these CPT1mt-protective effects in dbTg-HFHS mice were associated with preserved muscle insulin signaling, increased muscle glycogen content, and upregulation of key genes involved in muscle glucose metabolism. These beneficial effects of muscle CPT1mt expression suggest that a direct modulation of the malonyl-CoA/CPT1 partnership in skeletal muscle could represent a potential strategy to prevent obesity-induced insulin resistance.
2004-10-28 | Differential carnitine/acylcarnitine translocase expression defines distinct metabolic signatures in skeletal muscle cells
Abstract Import of acylcarnitine into mitochondrial matrix through carnitine/acylcarnitine‐translocase (CACT) is fundamental for lipid catabolism. To probe the effect of CACT down‐expression on lipid metabolism in muscle, human myocytes were stably transfected with CACT‐antisense construct. In presence of low concentration of palmitate, transfected cells showed decreased palmitate oxidation and acetyl‐carnitine content, increased palmitoyl‐carnitine level, and reduced insulin‐dependent decrease of fatty acylcarnitine‐to‐fatty acyl‐CoA ratio. The augmented palmitoyl‐carnitine synthesis, also in the presence of insulin, could be related to an altered regulation of carnitine‐palmitoyl‐transferase 1 (CPT 1) by malonyl‐CoA, whose synthesis is dependent by the availability of cytosolic acetyl‐groups. Indeed, all the described effects were completely overcome by CACT neo‐expression by recombinant adenovirus vector or by addition of acetyl‐carnitine to cultures. Acetyl‐carnitine effect was related to an increase of malonyl‐CoA and was abolished by down‐expression, via antisense RNA strategy, of acetyl‐CoA carboxylase‐β, the mitochondrial membrane enzyme involved in the direct CPT 1 inhibition via malonyl‐CoA synthesis. Thus, in our experimental model the modulation of CACT expression has consequences for CPT 1 activity, while the biologic effects of acetyl‐carnitine are not associated with a generic supply of energy compounds but to the anaplerotic property of the molecule. © 2004 Wiley‐Liss, Inc.
cell therapies
2023-05-01 | Implantation of CPT1AM-expressing adipocytes reduces obesity and glucose intolerance in mice
Obesity and its associated metabolic comorbidities are a rising global health and social issue, with novel therapeutic approaches urgently needed. Adipose tissue plays a key role in the regulation of energy balance and adipose tissue-derived mesenchymal stem cells (AT-MSCs) have gained great interest in cell therapy. Carnitine palmitoyltransferase 1A (CPT1A) is the gatekeeper enzyme for mitochondrial fatty acid oxidation. Here, we aimed to generate adipocytes expressing a constitutively active CPT1A form (CPT1AM) that can improve the obese phenotype in mice after their implantation. AT-MSCs were differentiated into mature adipocytes, subjected to lentivirus-mediated expression of CPT1AM or the GFP control, and subcutaneously implanted into mice fed a high-fat diet (HFD). CPT1AM-implanted mice showed lower body weight, hepatic steatosis and serum insulin and cholesterol levels alongside improved glucose tolerance. HFD-induced increases in adipose tissue hypertrophy, fibrosis, inflammation, endoplasmic reticulum stress and apoptosis were reduced in CPT1AM-implanted mice. In addition, the expression of mitochondrial respiratory chain complexes was enhanced in the adipose tissue of CPT1AM-implanted mice. Our results demonstrate that implantation of CPT1AM-expressing AT-MSC-derived adipocytes into HFD-fed mice improves the obese metabolic phenotype, supporting the future clinical use of this ex vivo gene therapy approach.
2013-05-07 | Lactobacillus reuteri prevents diet-induced obesity, but not atherosclerosis, in a strain dependent fashion in Apoe-/- mice.
To investigate whether the specific strains of Lactobacillus reuteri modulates the metabolic syndrome in Apoe-/- mice. 8 week-old Apoe-/- mice were subdivided into four groups who received either L. reuteri ATCC PTA 4659 (ATCC), DSM 17938 (DSM), L6798, or no bacterial supplement in the drinking water for 12 weeks. The mice were fed a high-fat Western diet with 0.2% cholesterol and body weights were monitored weekly. At the end of the study, oral glucose and insulin tolerance tests were conducted. In addition, adipose and liver weights were recorded along with analyses of mRNA expression of ileal Angiopoietin-like protein 4 (Angptl4), the macrophage marker F4/80 encoded by the gene Emr1 and liver Acetyl-CoA carboxylase 1 (Acc1), Fatty acid synthase (Fas) and Carnitine palmitoyltransferase 1a (Cpt1a). Atherosclerosis was assessed in the aortic root region of the heart. Mice receiving L. reuteri ATCC gained significantly less body weight than the control mice, whereas the L6798 mice gained significantly more. Adipose and liver weights were also reduced in the ATCC group. Serum insulin levels were lower in the ATCC group, but no significant effects were observed in the glucose or insulin tolerance tests. Lipogenic genes in the liver were not altered by any of the bacterial treatments, however, increased expression of Cpt1a was found in the ATCC group, indicating increased β-oxidation. Correspondingly, the liver trended towards having lower fat content. There were no effects on inflammatory markers, blood cholesterol or atherosclerosis. In conclusion, the probiotic L. reuteri strain ATCC PTA 4659 partly prevented diet-induced obesity, possibly via a previously unknown mechanism of inducing liver expression of Cpt1a.
oligonucleotides
2023-08-21 | ApoE expression in macrophages communicates immunometabolic signaling that controls hyperlipidemia-driven hematopoiesis & inflammation via extracellular vesicles.
While apolipoprotein E (apoE) expression by myeloid cells is recognized to control inflammation, whether such benefits can be communicated via extracellular vesicles is not known. Through the study of extracellular vesicles produced by macrophages derived from the bone marrow of Wildtype (WT-BMDM-EV) and ApoE deficient (EKO-BMDM-EV) mice, we uncovered a critical role for apoE expression in regulating their cell signaling properties. WT-BMDM-EV communicated anti-inflammatory properties to recipient myeloid cells by increasing cellular levels of apoE and miR-146a-5p, that reduced NF-κB signalling. They also downregulated cellular levels of miR-142a-3p, resulting in increased levels of its target carnitine palmitoyl transferase 1A (CPT1A) which improved fatty acid oxidation (FAO) and oxidative phosphorylation (OxPHOS) in recipient cells. Such favorable metabolic polarization enhanced cell-surface MerTK levels and the phagocytic uptake of apoptotic cells. In contrast, EKO-BMDM-EV exerted opposite effects by reducing cellular levels of apoE and miR-146a-5p, which increased NF-κB-driven GLUT1-mediated glucose uptake, aerobic glycolysis, and oxidative stress. Furthermore, EKO-BMDM-EV increased cellular miR-142a-3p levels, which reduced CPT1A levels and impaired FAO and OxPHOS in recipient myeloid cells. When cultured with naïve CD4+ T lymphocytes, EKO-BMDM-EV drove their activation and proliferation, and fostered their transition to a Th1 phenotype. While infusions of WT-BMDM-EV into hyperlipidemic mice resolved inflammation, infusions of EKO-BMDM-EV increased hematopoiesis and drove inflammatory responses in myeloid cells and T lymphocytes. ApoE-dependent immunometabolic signaling by macrophage extracellular vesicles was dependent on transcriptional axes controlled by miR-146a-5p and miR-142a-3p that could be reproduced by infusing miR-146a mimics & miR-142a antagonists into hyperlipidemic apoE-deficient mice. Together, our findings unveil a novel property for apoE expression in macrophages that modulates the immunometabolic regulatory properties of their secreted extracellular vesicles.
small molecules
2026-04-13 | UFL1 deficiency disrupts skeletal muscle lipid metabolism by promoting the ACC1-FASN axis.
Skeletal muscle lipid metabolic homeostasis is essential for normal function and physical performance. Ubiquitin-fold modifier 1 ligase 1 (UFL1), the sole E3 ligase in the UFMylation system, is widely involved in lipid metabolism across various cell types, yet its specific role in skeletal muscle remains unclear. Using skeletal muscle-specific UFL1 knockout mice and UFL1-manipulated C2C12 cells, we found that UFL1 deficiency led to marked lipid droplet accumulation, elevated triglyceride (TG) and total cholesterol (TCH) levels, and upregulation of the lipid droplet coat protein perilipin 2 (PLIN2), whereas UFL1 overexpression reversed these effects. Mechanistically, expression of the lipogenic enzymes acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN) was significantly increased in UFL1-deficient tissues and cells, whereas protein levels of peroxisome proliferator-activated receptor alpha (PPARα) and its downstream target carnitine palmitoyltransferase 1A (CPT1A) remained unchanged, effects reversed by UFL1 overexpression. Collectively, these findings establish UFL1 as a critical regulator of skeletal muscle lipid homeostasis through the ACC1-FASN axis, independent of fatty acid oxidation, revealing a novel target for treating skeletal muscle lipid metabolic dysfunction.
2026-04-02 | Cardiolipin alleviates insulin resistance by ameliorating mitochondrial dysfunction and promoting fatty acid oxidation.
Cardiolipin deficiency is closely associated with mitochondrial dysfunction and metabolic disorders, yet whether it directly modulates insulin resistance remains unknown. Here, we examined the effects of cardiolipin supplementation on insulin resistance and the underlying mechanisms using male C57BL/6J mice fed a high-fat diet, male db/db mice, and dexamethasone-induced insulin-resistant HepG2 cells, a well-established model for investigating hepatic insulin signaling. Intragastric administration of cardiolipin at 5 mg/kg lowered blood glucose, reduced weight gain, improved insulin sensitivity, and alleviated hepatic lipid accumulation in mice, along with decreased serum interleukin-6 and low-density lipoprotein cholesterol levels. Cardiolipin reduced the LC3-II/LC3-I ratio and Tom20 expression in both liver tissue and insulin-resistant HepG2 cells, indicative of enhanced mitophagy. In HepG2 cells, it also attenuated mitochondrial fragmentation, improved mitochondrial membrane potential, lowered reactive oxygen species production, and upregulated the expression of CPT1A and ACAD1. These findings demonstrate that cardiolipin mitigates hepatic insulin resistance by enhancing mitophagy and fatty acid oxidation, representing a promising therapeutic approach for insulin resistance-related metabolic disorders.
2026-03-14 | Betulinic Acid Attenuates Vascular Smooth Muscle Cell Senescence and Aortic Vascular Aging via PPAR-α/CPT1A-Mediated Fatty Acid Oxidation.
Vascular stiffness and aging are critical contributors to cardiovascular diseases. Whether betulinic acid (BA), a natural triterpenoid, alleviates vascular aging remains unclear. Mouse aortic smooth muscle cells (MASMCs) with oleic acid (OA)-induced lipotoxic senescence were treated with BA (30 μM). Transcriptomic analysis and functional assays were conducted. In vivo, ApoE-/- mice fed a high-fat diet received oral BA (25 mg/kg/day) for 14 weeks. OA-induced lipotoxic senescence was associated with overactivation of peroxisome proliferator-activated receptor alpha (PPAR-α)/fatty acid oxidation (FAO) signaling, which was attenuated by BA intervention. Molecular docking suggested that BA binds to the Arg226 site of PPAR-α, which was further supported by surface plasmon resonance analysis. BA significantly reduced OA-induced expression of P16, P21, and P53 (p < 0.05), inhibited reactive oxygen species generation, and improved mitochondrial function, indicating pronounced antisenescence effects of BA. Moreover, PPAR-α overexpression reversed these protective effects. In ApoE-/- mice, BA intervention reduced vascular pulse wave velocity (2.7 ± 0.32 vs. 3.3 ± 0.45 m/s, p < 0.05) and intima-media thickness (0.114 ± 0.012 vs. 0.137 ± 0.018 mm, p < 0.05). BA attenuates MASMC lipotoxic senescence and aortic metabolism-associated vascular aging by inhibiting PPAR-α/carnitine palmitoyl transferase 1A-mediated FAO, suggesting a potential metabolic-targeted strategy for preventing lipid-associated vascular aging.
2026-02-16 | Rubimaillin ameliorates liver fibrosis by triggering the ferroptosis of activated hepatic stellate cells through targeting CPT1A.
Liver fibrosis is defined as the excessive accumulation of extracellular matrix proteins in the liver due to chronic liver injury. Targeted ferroptosis of activated hepatic stellate cells (HSCs) is considered a promising therapeutic strategy for liver fibrosis. Rubimaillin (Rub), a naphthoquinone compound extracted from traditional Chinese medicine Rubia cordifolia L., exhibits various activities in multiple diseases. This study aimed to investigate the anti-hepatic fibrosis effect, the direct protein target, and molecular mechanism of Rub. Here, our results demonstrated that Rub effectively ameliorated liver fibrosis via triggering the ferroptosis of activated HSCs in mice models. Subsequently, we confirmed that Rub directly binds to carnitine palmitoyltransferase 1A (CPT1A) at SER592, THR594, and THR689, and inhibits its activity using PROTAC technology, computer molecular dynamics simulations, CETSA, DARTS, BLI, and site mutation assays. Further, the inhibition or deficiency of CPT1A in activated HSCs could trigger metabolic reprogramming-mediated ferroptosis. Moreover, CPT1A deficiency or overexpression could eliminate the effects of Rub-induced ferroptosis. Mechanistically, Rub-induced ferroptosis in activated HSCs was associated with metabolic reprogramming mediated by targeting CPT1A. Taken together, our results indicate the beneficial effects, the direct protein target and the molecular mechanism via which Rub induces ferroptosis in activated HSCs to ameliorate liver fibrosis.
2026-01-15 | Brown adipocyte-derived SAA3-CPT1A axis regulates diet-induced thermogenesis and protects against obesity.
Diet-induced thermogenesis (DIT), a critical component of energy expenditure driven by brown adipose tissue (BAT), is essential for maintaining metabolic health; however, its precise molecular regulation remains poorly understood. We investigated whether serum amyloid A3 (SAA3), a factor secreted by brown adipocytes, regulates DIT and protects against diet-induced obesity. Using two distinct mouse models: mice with brown adipocyte-specific Saa3 deletion and mice with lentiviral-mediated Saa3 overexpression in BAT, we examined energy expenditure, substrate utilization, and thermogenic responses under chow or short-term high-fat diet feeding. SAA3 expression in BAT was acutely induced by refeeding. Loss of SAA3 severely diminished postprandial DIT and total energy expenditure, leading to accelerated weight gain on a high-fat diet. Mechanistically, Saa3 deletion compromised uncoupling protein‑1 induction, chiefly by impairing adipose triglyceride lipase-driven lipolysis and, critically, by inhibiting carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation (FAO). Conversely, SAA3 overexpression robustly enhanced DIT, stimulated lipolysis and FAO, and promoted mitochondrial oxidative phosphorylation. Studies in primary brown adipocytes confirmed that SAA3 deficiency reduced CPT1A expression, palmitate-stimulated lipolysis, and mitochondrial respiration. Together, these findings identify the SAA3-CPT1A axis as a novel, BAT-intrinsic mechanism that couples nutrient sensing to uncoupling protein‑11 function via enhanced FAO. By promoting lipid utilization and postprandial energy dissipation, SAA3 optimizes postprandial thermogenesis and defends against obesity, highlighting conserved SAA signaling as a potential nutritional and therapeutic target in metabolic disease.
gene therapies
2025-06-12 | Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers ApoB-Containing Lipoproteins in Mice.
Genome- and epigenome-wide association studies have associated variants and methylation status of CPT1a (carnitine palmitoyltransferase 1a) to reductions in VLDL (very low-density lipoprotein) cholesterol and triglyceride levels. The objective of this study was to determine the mechanisms by which CPT1a-dependent mitochondrial fatty acid oxidation influences hepatic and lipoprotein metabolism. Eight-week-old male and female Cpt1a-floxed mice (Cpt1afl/fl) and Cpt1a-floxed mice expressing the human apo B100 transgene (Cpt1afl/fl/B100Tg) were administered control adeno-associated virus or adeno-associated virus encoding Cre-recombinase under control of a liver-specific promoter (TBG-Cre [thyroxin-binding globulin]). Control and liver-specific knockout mice were placed on a low-fat control or western-type diet (42% kcal fat, 0.2% cholesterol) for 16 weeks. Livers were collected and used for histological and lipid analysis, while gene and protein expression were measured by bulk RNA-sequencing and immunoblotting, respectively. Lipoprotein composition in plasma was determined by size exclusion chromatography and nuclear magnetic resonance. Rates of VLDL-triglyceride secretion were quantified after lipase inhibition with poloxamer 407. Liquid and gas chromatography-mass spectrometry were used to measure bile acid species and fecal neutral sterols, respectively. We report significant associations between the presence of CPT1a SNPs (single nucleotide polymorphisms) and reductions in plasma cholesterol, as well as positive associations between hepatic Cpt1a expression and plasma cholesterol levels across inbred mouse strains. Mechanistic studies show that both wild-type and human apo B100 (apoB)-transgenic mice with liver-specific deletion of Cpt1a (liver-specific knockout) display lower circulating apoB levels consistent with reduced LDL (low-density lipoprotein)-cholesterol and LDL particle number. Despite a reduction in steady-state plasma lipids, VLDL-triglyceride and VLDL cholesterol secretion rates are increased, suggesting accelerated clearance of apoB-LPs (apoB-containing lipoproteins) in liver-specific knockout mice. Mechanistic approaches show greater PPARα (peroxisome proliferator-activated receptor α) signaling which favors enhanced lipoprotein lipase-mediated metabolism of apoB-LPs, including increases in apo AIV and apo CII and reductions in apo CIII and Angptl3 (angiopoietin-like 3). These studies provide mechanistic insight linking genetic variants and methylation status of CPT1a to reductions in circulating apoB-LPs in humans.
2025-01-07 | Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers Apolipoprotein B Containing Lipoproteins in Mice.
Genome- and epigenome-wide association studies have associated variants and methylation status of carnitine palmitoyltransferase 1a (CPT1a) to reductions in very low-density lipoprotein (VLDL) cholesterol and triglyceride levels. We report significant associations between the presence of CPT1a SNPs and reductions in plasma cholesterol, as well as positive associations between hepatic Cpt1a expression and plasma cholesterol levels across inbred mouse strains. Mechanistic studies show that both wild type and human apolipoprotein B100 (apoB)-transgenic mice with liver-specific deletion of Cpt1a (LKO) display lower circulating apoB levels consistent with reduced LDL-cholesterol (LDL-C) and LDL particle number. Despite a reduction in steady-state plasma lipids, VLDL-triglyceride (VLDL-TG) and cholesterol (VLDL-C) secretion rates are increased, suggesting accelerated clearance of apoB-containing lipoproteins (apoB-LPs) in LKO mice. Mechanistic approaches show greater peroxisome proliferator activated receptor α (PPARα) signaling which favors enhanced lipoprotein lipase-mediated metabolism of apoB-LPs, including increases in ApoCII and ApoAIV and reductions in ApoCIII & Angptl3. These studies provide mechanistic insight linking genetic variants and methylation status of CPT1a to reductions in circulating apoB-LPs in humans. Loss-of-function SNPs in CPT1a associate with reductions in plasma cholesterol in humans Hepatic Cpt1a expression positively associates with plasma cholesterol levels across inbred strains of miceLiver-specific Cpt1a deficiency lowers circulating apoB, plasma cholesterol, LDL-C, and LDL particle numberCpt1a ablation activates PPARα and favors clearance of apoB-containing lipoproteins.
2016-08-09 | Muscle expression of a malonyl-CoA-insensitive carnitine palmitoyltransferase-1 protects mice against high-fat/high-sucrose diet-induced insulin resistance
Impaired skeletal muscle mitochondrial fatty acid oxidation (mFAO) has been implicated in the etiology of insulin resistance. Carnitine palmitoyltransferase-1 (CPT1) is a key regulatory enzyme of mFAO whose activity is inhibited by malonyl-CoA, a lipogenic intermediate. Whereas increasing CPT1 activity in vitro has been shown to exert a protective effect against lipid-induced insulin resistance in skeletal muscle cells, only a few studies have addressed this issue in vivo. We thus examined whether a direct modulation of muscle CPT1/malonyl-CoA partnership is detrimental or beneficial for insulin sensitivity in the context of diet-induced obesity. By using a Cre- LoxP recombination approach, we generated mice with skeletal muscle-specific and inducible expression of a mutated CPT1 form (CPT1mt) that is active but insensitive to malonyl-CoA inhibition. When fed control chow, homozygous CPT1mt transgenic (dbTg) mice exhibited decreased CPT1 sensitivity to malonyl-CoA inhibition in isolated muscle mitochondria, which was sufficient to substantially increase ex vivo muscle mFAO capacity and whole body fatty acid utilization in vivo. Moreover, dbTg mice were less prone to high-fat/high-sucrose (HFHS) diet-induced insulin resistance and muscle lipotoxicity despite similar body weight gain, adiposity, and muscle malonyl-CoA content. Interestingly, these CPT1mt-protective effects in dbTg-HFHS mice were associated with preserved muscle insulin signaling, increased muscle glycogen content, and upregulation of key genes involved in muscle glucose metabolism. These beneficial effects of muscle CPT1mt expression suggest that a direct modulation of the malonyl-CoA/CPT1 partnership in skeletal muscle could represent a potential strategy to prevent obesity-induced insulin resistance.
2004-10-28 | Differential carnitine/acylcarnitine translocase expression defines distinct metabolic signatures in skeletal muscle cells
Abstract Import of acylcarnitine into mitochondrial matrix through carnitine/acylcarnitine‐translocase (CACT) is fundamental for lipid catabolism. To probe the effect of CACT down‐expression on lipid metabolism in muscle, human myocytes were stably transfected with CACT‐antisense construct. In presence of low concentration of palmitate, transfected cells showed decreased palmitate oxidation and acetyl‐carnitine content, increased palmitoyl‐carnitine level, and reduced insulin‐dependent decrease of fatty acylcarnitine‐to‐fatty acyl‐CoA ratio. The augmented palmitoyl‐carnitine synthesis, also in the presence of insulin, could be related to an altered regulation of carnitine‐palmitoyl‐transferase 1 (CPT 1) by malonyl‐CoA, whose synthesis is dependent by the availability of cytosolic acetyl‐groups. Indeed, all the described effects were completely overcome by CACT neo‐expression by recombinant adenovirus vector or by addition of acetyl‐carnitine to cultures. Acetyl‐carnitine effect was related to an increase of malonyl‐CoA and was abolished by down‐expression, via antisense RNA strategy, of acetyl‐CoA carboxylase‐β, the mitochondrial membrane enzyme involved in the direct CPT 1 inhibition via malonyl‐CoA synthesis. Thus, in our experimental model the modulation of CACT expression has consequences for CPT 1 activity, while the biologic effects of acetyl‐carnitine are not associated with a generic supply of energy compounds but to the anaplerotic property of the molecule. © 2004 Wiley‐Liss, Inc.
cell therapies
2023-05-01 | Implantation of CPT1AM-expressing adipocytes reduces obesity and glucose intolerance in mice
Obesity and its associated metabolic comorbidities are a rising global health and social issue, with novel therapeutic approaches urgently needed. Adipose tissue plays a key role in the regulation of energy balance and adipose tissue-derived mesenchymal stem cells (AT-MSCs) have gained great interest in cell therapy. Carnitine palmitoyltransferase 1A (CPT1A) is the gatekeeper enzyme for mitochondrial fatty acid oxidation. Here, we aimed to generate adipocytes expressing a constitutively active CPT1A form (CPT1AM) that can improve the obese phenotype in mice after their implantation. AT-MSCs were differentiated into mature adipocytes, subjected to lentivirus-mediated expression of CPT1AM or the GFP control, and subcutaneously implanted into mice fed a high-fat diet (HFD). CPT1AM-implanted mice showed lower body weight, hepatic steatosis and serum insulin and cholesterol levels alongside improved glucose tolerance. HFD-induced increases in adipose tissue hypertrophy, fibrosis, inflammation, endoplasmic reticulum stress and apoptosis were reduced in CPT1AM-implanted mice. In addition, the expression of mitochondrial respiratory chain complexes was enhanced in the adipose tissue of CPT1AM-implanted mice. Our results demonstrate that implantation of CPT1AM-expressing AT-MSC-derived adipocytes into HFD-fed mice improves the obese metabolic phenotype, supporting the future clinical use of this ex vivo gene therapy approach.
2013-05-07 | Lactobacillus reuteri prevents diet-induced obesity, but not atherosclerosis, in a strain dependent fashion in Apoe-/- mice.
To investigate whether the specific strains of Lactobacillus reuteri modulates the metabolic syndrome in Apoe-/- mice. 8 week-old Apoe-/- mice were subdivided into four groups who received either L. reuteri ATCC PTA 4659 (ATCC), DSM 17938 (DSM), L6798, or no bacterial supplement in the drinking water for 12 weeks. The mice were fed a high-fat Western diet with 0.2% cholesterol and body weights were monitored weekly. At the end of the study, oral glucose and insulin tolerance tests were conducted. In addition, adipose and liver weights were recorded along with analyses of mRNA expression of ileal Angiopoietin-like protein 4 (Angptl4), the macrophage marker F4/80 encoded by the gene Emr1 and liver Acetyl-CoA carboxylase 1 (Acc1), Fatty acid synthase (Fas) and Carnitine palmitoyltransferase 1a (Cpt1a). Atherosclerosis was assessed in the aortic root region of the heart. Mice receiving L. reuteri ATCC gained significantly less body weight than the control mice, whereas the L6798 mice gained significantly more. Adipose and liver weights were also reduced in the ATCC group. Serum insulin levels were lower in the ATCC group, but no significant effects were observed in the glucose or insulin tolerance tests. Lipogenic genes in the liver were not altered by any of the bacterial treatments, however, increased expression of Cpt1a was found in the ATCC group, indicating increased β-oxidation. Correspondingly, the liver trended towards having lower fat content. There were no effects on inflammatory markers, blood cholesterol or atherosclerosis. In conclusion, the probiotic L. reuteri strain ATCC PTA 4659 partly prevented diet-induced obesity, possibly via a previously unknown mechanism of inducing liver expression of Cpt1a.
oligonucleotides
2023-08-21 | ApoE expression in macrophages communicates immunometabolic signaling that controls hyperlipidemia-driven hematopoiesis & inflammation via extracellular vesicles.
While apolipoprotein E (apoE) expression by myeloid cells is recognized to control inflammation, whether such benefits can be communicated via extracellular vesicles is not known. Through the study of extracellular vesicles produced by macrophages derived from the bone marrow of Wildtype (WT-BMDM-EV) and ApoE deficient (EKO-BMDM-EV) mice, we uncovered a critical role for apoE expression in regulating their cell signaling properties. WT-BMDM-EV communicated anti-inflammatory properties to recipient myeloid cells by increasing cellular levels of apoE and miR-146a-5p, that reduced NF-κB signalling. They also downregulated cellular levels of miR-142a-3p, resulting in increased levels of its target carnitine palmitoyl transferase 1A (CPT1A) which improved fatty acid oxidation (FAO) and oxidative phosphorylation (OxPHOS) in recipient cells. Such favorable metabolic polarization enhanced cell-surface MerTK levels and the phagocytic uptake of apoptotic cells. In contrast, EKO-BMDM-EV exerted opposite effects by reducing cellular levels of apoE and miR-146a-5p, which increased NF-κB-driven GLUT1-mediated glucose uptake, aerobic glycolysis, and oxidative stress. Furthermore, EKO-BMDM-EV increased cellular miR-142a-3p levels, which reduced CPT1A levels and impaired FAO and OxPHOS in recipient myeloid cells. When cultured with naïve CD4+ T lymphocytes, EKO-BMDM-EV drove their activation and proliferation, and fostered their transition to a Th1 phenotype. While infusions of WT-BMDM-EV into hyperlipidemic mice resolved inflammation, infusions of EKO-BMDM-EV increased hematopoiesis and drove inflammatory responses in myeloid cells and T lymphocytes. ApoE-dependent immunometabolic signaling by macrophage extracellular vesicles was dependent on transcriptional axes controlled by miR-146a-5p and miR-142a-3p that could be reproduced by infusing miR-146a mimics & miR-142a antagonists into hyperlipidemic apoE-deficient mice. Together, our findings unveil a novel property for apoE expression in macrophages that modulates the immunometabolic regulatory properties of their secreted extracellular vesicles.
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
1 orphan drug designation for Carnitine palmitoyl transferase 1A deficiency.
1 orphan drug designation for Carnitine palmitoyl transferase 1A deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Triheptanoin | small molecules | EMA | 2020-11-13 | — | Ultragenyx Netherlands B.V. |
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.