RARE DISEASE
Primary triglyceride deposit cardiomyovasculopathy
Primary triglyceride deposit cardiomyovasculopathy
Primary triglyceride deposit cardiomyovasculopathy
Synonyms: Neutral lipid storage disease with severe cardiovascular involvement, TGCV
Synonyms: Neutral lipid storage disease with severe cardiovascular involvement, TGCV
Synonyms: Neutral lipid storage disease with severe cardiovascular involvement, TGCV
Drug discovery
0
drugs
With orphan designations
Overview
Primary Triglyceride Deposit Cardiomyovasculopathy (TGCV) is a rare metabolic disorder characterized by defective intracellular triglyceride (TG) hydrolysis due to adipose triglyceride lipase (ATGL) mutations, leading to myocardial and coronary TG accumulation. This results in progressive heart failure, diffuse coronary artery narrowing, and high cardiovascular mortality. Diagnosis relies on imaging (BMIPP scintigraphy or 1H-MRS) and clinical criteria, with Jordans' anomaly in leukocytes supporting primary TGCV [1][2][5][6].
Categories: rare cardiac diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
33 drug discovery papers about Primary triglyceride deposit cardiomyovasculopathy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
33 drug discovery papers about Primary triglyceride deposit cardiomyovasculopathy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-04-15 | Triglyceride deposit cardiomyovasculopathy: A new class of cardiovascular disease.
Triglyceride (TG) deposit cardiomyovasculopathy (TGCV) was first identified in Japanese patients with homozygous mutations in PNPLA2 encoding adipose triglyceride lipase. TGs and fatty acids released by lipolytic action are major energy substrates in a normal heart. In TGCV, the defective intracellular lipolysis of long-chain TGs causes cellular steatosis and energy failure mainly in cardiomyocytes and vascular smooth muscle cells. One of the major characteristics is diffuse narrowing TG-deposited coronary atherosclerosis which is distinct from classic cholesterol-induced focal lesions. TGCV comprises primary and idiopathic subtypes with and without homozygous PNPLA2 mutations, respectively. Genetic causes or backgrounds of idiopathic TGCV (I-TGCV) remain undetermined. We established the diagnostic criteria without requirement of genetic tests, including the reduced washout rate (<10%) of iodine-123-β-methyl-p-iodophenyl-pentadecanoic acid in myocardial single-photon emission computed tomography, which reflects defective lipolysis, as an essential item. Serum TG level and body mass index are irrelevant to the diagnosis. As of October 2024, 15 primary TGCV (P-TGCV) and 976 I-TGCV cases were diagnosed across all Japanese prefectures. The cardiac symptoms of P-TGCV and I-TGCV occurred in patients aged in their 30s and 50s, respectively. The patients exhibited heart failure (HF), diffuse coronary artery disease including vasospastic angina, and ventricular arrhythmia. The prognosis was very severe in patients with P-TGCV manifesting HF with reduced ejection fraction unless receiving cardiac transplantation. In I-TGCV, the 5-year-overall and cardiovascular event-free survival rates were 71.8% and 54.0%, respectively, with standard remedies. Tricaprin/trisdecanoin, a medium-chain TG that facilitates myocardial lipolysis, is being developed as a first-in-class orphan drug for TGCV. TGCV is a novel class of adult-onset cardiovascular disease caused by the defective lipolysis of long-chain TGs. Many patients with TGCV exhibiting high cardiovascular risk remain undiagnosed; thus, increased awareness of this emerging disease is required among cardiologists of all subspecialties.
2025-02-14 | Long-term survival and durable recovery of heart failure in patients with triglyceride deposit cardiomyovasculopathy treated with tricaprin.
Heart disease is a major global threat. Triglyceride deposit cardiomyovasculopathy (TGCV) is an emerging, noncommunicable, adult-onset heart disease, first identified in Japanese patients with heart failure (HF) requiring cardiac transplantation1-3. In TGCV, defective intracellular lipolysis of long-chain triglycerides (TGs) results in cellular steatosis and energy failure mainly in cardiomyocytes4 and smooth muscle cells5, leading to HF, diffuse coronary artery disease with TG deposition and ventricular arrhythmias with high mortality6. Tricaprin, a class of medium-chain TGs, recently corrected myocardial TG lipolysis7. Here we report remarkable long-term survival and durable recovery of HF in patients with TGCV treated with supplemental tricaprin in registry studies. Our study offers a classification of heart disease caused by defective lipolysis and its possible practical treatment. Because myocardial lipid droplets are a common feature in HF and their potential as therapeutic targets has been discussed worldwide, our findings warrant investigation into other ethnicities.
2024-12-23 | Detection of triglyceride metabolism in white blood cells using a novel fluorescently labeled long chain fatty acid analogue
Abstract 123 I-15-(p-iodophenyl)-( R , S )-methyl pentadecanoic acid ( 123 I-BMIPP) is a long-chain fatty acid (LCFA) analog developed to examine myocardial LCFA metabolism and has been used as a tracer for nuclear cardiology. However, its use is limited because of the specialized features of cardiac scintigraphy. In this study, a novel BMIPP-based probe, in which iodine-123 was replaced with a fluorescent compound, was used to extend the application of 123 I-BMIPP to ex vivo analysis of fatty acid metabolism. To confirm that fluorescently labeled BMIPP-based probe (fluorescent BMPP) is effective for the detection of LCFA metabolism ex vivo , we performed fluorescence-activated cell sorting (FACS) analysis for the incorporation of fluorescent BMPP using white blood cells from human peripheral blood. FACS analysis showed that the incorporation of fluorescent BMPP into white blood cells was dose-dependent. Fluorescence intensities of cells incorporating fluorescent BMPP were attenuated after incubation in non-fluorescent BMPP medium, suggesting that these cells could export the probe. Neutrophils from a patient with primary triglyceride deposit cardiomyovasculopathy, a rare type of triglyceride (TG) metabolism disorders, showed lower BMPP export and was ameliorated after treatment with tricaprin. These results suggest that fluorescent BMPP could be imported to and exported from cells through the same mechanism as 123 I-BMIPP, reflecting the mechanism that occurs for LCFAs during TG metabolism. This study shows that fluorescent BMPP has the potential to be used as a probe for the diagnosis of TG metabolic diseases ex vivo .
2024-11-12 | Abstract 4139747: Inhibition of Acetyl -CoA Carboxylase 2 (ACC2) enhances fatty acid oxidation and improves cardiac function and survival in a severe model of heart failure
Heart failure (HF) is characterized by disordered energy metabolism including impaired mitochondrial oxidation and altered energy substrate preference. In triglyceride (TG) deposit cardiomyovasculopathy (TGCV; ORPHA code 565612), a rare form of HF characterized by impaired fatty acid oxidation (FAO), massive TG accumulation occurs in cardiac muscle and vasculature due to deficiency of adipose triglyceride lipase (ATGL). Since acetyl-CoA carboxylase 2 (ACC2) regulates fatty acid transport into mitochondria for oxidation, we hypothesized that genetic deletion or pharmacologic inhibition of ACC2 may improve cardiac function in the Atgl knockout (KO) mouse model of TGCV. Relative to Atgl KO mice, Atgl/Acc2 double KO mice had reduced cardiac TG accumulation and fibrosis, and significant improvements in cardiac function by echocardiography, locomotor activity, and survival (log-rank p <0.0001). These findings were recapitulated by treatment of Atgl KO mice with TLC-3595, a highly selective, systemic, small molecule ACC2 inhibitor in development for type 2 diabetes ( Figure ). After a single dose of TLC-3595 to Atgl KO mice, dose-dependent reductions in cardiac malonyl-CoA levels and TG content were observed. Further, in a detailed time-course echocardiographic analysis, Atgl KO mice had reduced left ventricular ejection fraction and evidence of cardiac remodeling which was ameliorated by TLC-3595 treatment. Metabolomic profiling of cardiac tissue revealed ACC2-specific changes, including reduced malonyl-CoA and increased acylcarnitines, consistent with increased FAO with TLC-3595 treatment. Moreover, levels of TCA cycle metabolites and acetylcarnitine were reduced in Atgl KO mice but increased with ACC2 deletion or TLC-3595. In summary, ACC2 deletion or pharmacologic inhibition restored cardiac energy metabolism towards increased FAO in Atgl KO mice, resulting in improved cardiac function and survival. These findings support the therapeutic targeting of ACC2, including with the selective small molecule ACC2 inhibitor TLC-3595, for the treatment of patients with HF associated with FAO deficiency.
2024-10-01 | Improvement of myocardial lipolysis in iodine-123-beta-methyl-P-iodophenyl-pentadecanoic acid scintigraphy in patients with idiopathic triglyceride deposit cardiomyovasculopathy treated with Tricaprin
Abstract Background Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare intractable cardiovascular disorder (Orphanet ORPHAcode: 565612) in which defective intracellular lipolysis results in heart failure and coronary artery disease. Myocardial scintigraphy with iodine-123-β-methyl-P-iodophenyl-pentadecanoic acid (BMIPP) is useful for evaluating myocardial TG metabolism and its washout rate (WR) reflects myocardial lipolysis. A decreased WR (<10%) of BMIPP is one of the diagnostic criteria for TGCV. CNT-01, the active ingredient of which is tricaprin, a medium-chain triglyceride, has the potential to facilitate myocardial lipolysis in a mouse model. However, the effects of CNT-01 (tricaprin) on BMIPP scintigraphy in patients with TGCV remain unclear. Purpose To evaluate the effects of CNT-01 on BMIPP-WR in patients with TGCV. Methods An investigator-initiated, randomized, double-blind exploratory trial (Phase IIa) was conducted. Ten patients with idiopathic TGCV in our hospital were enrolled and orally administered 1.5 g/day of CNT-01 or placebo for 8 weeks. The endpoint was the delta WR on BMIPP scintigraphy. All the participants underwent BMIPP scintigraphy after overnight fasting. Following the protocol recommended by the Japanese Society of Nuclear Cardiology, 111 MBq of BMIPP was intravenously injected at rest after fasting for ≥ 12 h. Early and delayed images were obtained after 20 and 180–210 min, respectively. BMIPP scintigraphy at baseline and 8-week was performed using the same SPECT apparatus. WR is defined as the ratio of the difference between the counts in the early image and time-decay-corrected delayed image divided by the former. We used a recently proposed algorithm for calculating the WR based on the total count and analyzed the WRs (Ann Nucl Cardiol. 2023;9(1):19-25). Results A total of 5 patients were assigned to placebo and 5 patients were assigned to CNT-01. During the protocol, delta BMIPP-WRs were -6.18 ± 4.43 and 5.44 ± 2.57 % (95% confidence intervals, -12.33 to -0.03 and 1.88 to 9.00) in the placebo and CNT-01 groups, respectively. The baseline-adjusted difference in delta BMIPP-WR between the two groups was significant (p=0.005) (Picture). No significant changes were observed in clinical parameters. Conclusion This study demonstrated that CNT-01 improved myocardial lipolysis in patients with TGCV as measured by BMIPP scintigraphy.
gene therapies
2025-08-01 | Abstract Wed022: BSCL2/Seipin Deletion Rescues ATGL-deficiency-induced Lethal Lipotoxic Cardiomyopathy via Modulating Cardiac Lipid Droplet Proteome
Imbalances in triglyceride (TG) catabolism are closely associated with cardiac lipid deposition and contractile dysfunction, as observed in patients with primary triglyceride deposit cardiomyovasculopathy (TGCV) due to adipose triglyceride lipase (ATGL) deficiency. BSCL2/Seipin is a highly conserved protein in the endoplasmic reticulum that plays a key role in lipid droplet (LD) biogenesis and TG metabolism. We previously reported that deleting BSCL2 in the heart increased myocardial ATGL expression and decreased cardiac steatosis. However, the relationship between BSCL2 and ATGL in the heart still needs further investigation. In this study, we unexpectedly found that both global and cardiac-specific deletion of BSCL2 completely alleviated lethal lipotoxic cardiomyopathy in the genetic TGCV model ( Atgl −/− mice and mice with cardiac-specific deletion of Atgl , referred to as A cKO ) by significantly reducing cardiac TG deposits, eliminating cardiac hypertrophy, and restoring cardiac contractility. Transcriptomic analyses revealed elevated inflammation, oxidative stress, and fibrosis in Atgl −/− hearts, which were dramatically attenuated by BSCL2 deletion. Conversely, the severely impaired cardiac metabolic functions, muscle contraction, and ion transport in Atgl −/− hearts were remarkably improved by BSCL2 deletion. Notably, the markedly downregulated Pgc1 / Ppara and fatty acid oxidation genes in Atgl -deficient hearts were restored by BSCL2 deletion. Further deletion of Pparα reverted Atgl −/− Bscl2 −/− hearts to lethal lipotoxic cardiomyopathy, indicating its crucial role in the rescue effects mediated by BSCL2 deletion. To identify the pathways that activate PPARα in the absence of ATGL and BSCL2, we conducted quantitative myocardial LD proteomics and discovered distinct LD proteomes characterized by an increased targeting of several neutral lipid hydrolases including hormone sensitive lipase (HSL) to the LDs in hearts with cardiac-specific deletions of both Atgl and Bscl2 compared to A cKO hearts. These findings suggest cardiac BSCL2 autonomously regulates ATGL-independent neutral lipid metabolism essential for cardiac function by mobilizing the LD proteome. In conclusion, our study reveals novel mechanistic insights into the role of BSCL2 in the LD proteome and offers new therapeutic strategies for treating lethal triglyceride deposit cardiomyopathy.
2023-11-07 | Abstract 14505: BSCL2/Seipin Deletion Rescues ATGL-Deficiency-Induced Lethal Lipotoxic Cardiomyopathy
Imbalances in triglyceride (TG) catabolism are associated with cardiac lipid deposition and contractile dysfunction, as manifested in patients with primary triglyceride deposit cardiomyovasculopathy (TGCV) caused by adipose triglyceride lipase (ATGL) deficiency. BSCL2/Seipin is a highly conserved endoplasmic reticulum protein widely implicated in lipid droplet biogenesis and TG metabolism. We previously reported that global Bscl2 –/– mice and mice with cardiac-specific deletion of Bscl2 manifest higher myocardial ATGL expression and develop mild cardiomyopathy with reduced cardiac steatosis. However, the interplay between BSCL2 and ATGL in hearts remains to be further interrogated. In this study, we surprisingly discovered that global BSCL2 deletion completely rescued the lethal lipotoxic cardiomyopathy in the genetic ATGL-deficient TGCV model ( Atgl –/– mice) by drastically reducing cardiac TG deposits, abolishing cardiac hypertrophy, and restoring cardiac contractility. Transcriptomic analyses identified the elevated inflammatory, oxidative stress, and extracellular matrix pathways in Atgl –/– hearts, which were dramatically ameliorated by BSCL2 deletion. Conversely, the severely suppressed cardiac metabolic functions, muscle contraction, and ion transport pathways in Atgl –/– hearts were also normalized by BSCL2 deletion. Heatmap data further revealed that the mRNA levels of Pgc1/Ppara and fatty acid oxidation (FAO) genes were not altered in Bscl2 –/– hearts but were severely repressed in Atgl –/– hearts due to defective TG lipolysis. However, their expressions in Atgl –/– Bscl2 –/– hearts were restored to similar levels as wild-type and Bscl2 –/– hearts. RT-PCR analyses further confirmed such changes. Notably, cardiac-specific deletion of BSCL2 rescues lethal cardiomyopathy in mice with cardiac-specific deletion of ATGL. These data suggest that cardiac BSCL2 cell-autonomously regulates ATGL-independent TG hydrolysis and FAO pathways essential for cardiac function. Our study highlights the presence of BSCL2-mediated ATGL-independent pathways that regulate cardiac TG metabolism and provide novel therapeutic approaches to treat ATGL-deficiency-associated lethal cardiomyopathy.
2021-10-26 | Cardiac-specific CGI-58 deficiency activates the ER stress pathway to promote heart failure in mice
Excess myocardial triacylglycerol accumulation (i.e., cardiac steatosis) impairs heart function, suggesting that enzymes promoting triacylglycerol metabolism exert essential regulatory effects on heart function. Comparative gene identification 58 (CGI-58) is a key enzyme that promotes the hydrolysis of triglycerides by activating adipose triglyceride lipase and plays a protective role in maintaining heart function. In this study, the effects of CGI-58 on heart function and the underlying mechanism were investigated using cardiac-specific CGI58-knockout mice (CGI-58cko mice). Echocardiography and pathological staining were performed to detect changes in the structure and function of the heart. Proteomic profiling, immunofluorescent staining, western blotting, and real-time PCR were used to evaluate molecular changes. In CGI-58cko mice, we detected cardiac hypertrophic remodeling and heart failure associated with excessive cardiac lipid accumulation, ROS production, and decreased expression of regulators of fatty acid metabolism. These changes were markedly attenuated in CGI-58cko mice injected with rAAV9-CGI58. A quantitative proteomics analysis revealed significant increases in the expression of ER stress-related proteins and decreases in proteins related to fatty acid and amino acid metabolism in the hearts of CGI-58cko mice. Furthermore, the inhibition of ER stress by the inhibitor 4-PBA improved mitochondrial dysfunction, reduced oxidative stress, and reversed cardiac remodeling and dysfunction in cultured cardiomyocytes or in CGI-58cko mice. Our results suggested that CGI-58 is essential for the maintenance of heart function by reducing lipid accumulation and ER stress in cardiomyocytes, providing a new therapeutic target for cardiac steatosis and dysfunction.
proteins
2024-02-04 | Mfn2/Hsc70 Complex Mediates the Formation of Mitochondria‐Lipid Droplets Membrane Contact and Regulates Myocardial Lipid Metabolism
Abstract The heart primarily derives its energy through lipid oxidation. In cardiomyocytes, lipids are stored in lipid droplets (LDs) and are utilized in mitochondria, although the structural and functional connections between these two organelles remain largely unknown. In this study, visible evidence have presented indicating that a complex is formed at the mitochondria‐LD membrane contact (MLC) site, involving mitochondrion‐localized Mfn2 and LD‐localized Hsc70. This complex serves to tether mitochondria to LDs, facilitating the transfer of fatty acids (FAs) from LDs to mitochondria for β‐oxidation. Reduction of Mfn2 induced by lipid overload inhibits MLC, hinders FA transfer, and results in lipid accumulation. Restoring Mfn2 reinstates MLC, alleviating myocardial lipotoxicity under lipid overload conditions both in‐vivo and in‐vitro. Additionally, prolonged lipid overload induces Mfn2 degradation through the ubiquitin‐proteasome pathway, following Mfn2 acetylation at the K243 site. This leads to the transition from adaptive lipid utilization to maladaptive lipotoxicity. The experimental findings are supported by clinical data from patients with obesity and age‐matched non‐obese individuals. These translational results make a significant contribution to the molecular understanding of MLC in the heart, and offer new insights into its role in myocardial lipotoxicity.
small molecules
2026-04-15 | Triglyceride deposit cardiomyovasculopathy: A new class of cardiovascular disease.
Triglyceride (TG) deposit cardiomyovasculopathy (TGCV) was first identified in Japanese patients with homozygous mutations in PNPLA2 encoding adipose triglyceride lipase. TGs and fatty acids released by lipolytic action are major energy substrates in a normal heart. In TGCV, the defective intracellular lipolysis of long-chain TGs causes cellular steatosis and energy failure mainly in cardiomyocytes and vascular smooth muscle cells. One of the major characteristics is diffuse narrowing TG-deposited coronary atherosclerosis which is distinct from classic cholesterol-induced focal lesions. TGCV comprises primary and idiopathic subtypes with and without homozygous PNPLA2 mutations, respectively. Genetic causes or backgrounds of idiopathic TGCV (I-TGCV) remain undetermined. We established the diagnostic criteria without requirement of genetic tests, including the reduced washout rate (<10%) of iodine-123-β-methyl-p-iodophenyl-pentadecanoic acid in myocardial single-photon emission computed tomography, which reflects defective lipolysis, as an essential item. Serum TG level and body mass index are irrelevant to the diagnosis. As of October 2024, 15 primary TGCV (P-TGCV) and 976 I-TGCV cases were diagnosed across all Japanese prefectures. The cardiac symptoms of P-TGCV and I-TGCV occurred in patients aged in their 30s and 50s, respectively. The patients exhibited heart failure (HF), diffuse coronary artery disease including vasospastic angina, and ventricular arrhythmia. The prognosis was very severe in patients with P-TGCV manifesting HF with reduced ejection fraction unless receiving cardiac transplantation. In I-TGCV, the 5-year-overall and cardiovascular event-free survival rates were 71.8% and 54.0%, respectively, with standard remedies. Tricaprin/trisdecanoin, a medium-chain TG that facilitates myocardial lipolysis, is being developed as a first-in-class orphan drug for TGCV. TGCV is a novel class of adult-onset cardiovascular disease caused by the defective lipolysis of long-chain TGs. Many patients with TGCV exhibiting high cardiovascular risk remain undiagnosed; thus, increased awareness of this emerging disease is required among cardiologists of all subspecialties.
2025-02-14 | Long-term survival and durable recovery of heart failure in patients with triglyceride deposit cardiomyovasculopathy treated with tricaprin.
Heart disease is a major global threat. Triglyceride deposit cardiomyovasculopathy (TGCV) is an emerging, noncommunicable, adult-onset heart disease, first identified in Japanese patients with heart failure (HF) requiring cardiac transplantation1-3. In TGCV, defective intracellular lipolysis of long-chain triglycerides (TGs) results in cellular steatosis and energy failure mainly in cardiomyocytes4 and smooth muscle cells5, leading to HF, diffuse coronary artery disease with TG deposition and ventricular arrhythmias with high mortality6. Tricaprin, a class of medium-chain TGs, recently corrected myocardial TG lipolysis7. Here we report remarkable long-term survival and durable recovery of HF in patients with TGCV treated with supplemental tricaprin in registry studies. Our study offers a classification of heart disease caused by defective lipolysis and its possible practical treatment. Because myocardial lipid droplets are a common feature in HF and their potential as therapeutic targets has been discussed worldwide, our findings warrant investigation into other ethnicities.
2024-12-23 | Detection of triglyceride metabolism in white blood cells using a novel fluorescently labeled long chain fatty acid analogue
Abstract 123 I-15-(p-iodophenyl)-( R , S )-methyl pentadecanoic acid ( 123 I-BMIPP) is a long-chain fatty acid (LCFA) analog developed to examine myocardial LCFA metabolism and has been used as a tracer for nuclear cardiology. However, its use is limited because of the specialized features of cardiac scintigraphy. In this study, a novel BMIPP-based probe, in which iodine-123 was replaced with a fluorescent compound, was used to extend the application of 123 I-BMIPP to ex vivo analysis of fatty acid metabolism. To confirm that fluorescently labeled BMIPP-based probe (fluorescent BMPP) is effective for the detection of LCFA metabolism ex vivo , we performed fluorescence-activated cell sorting (FACS) analysis for the incorporation of fluorescent BMPP using white blood cells from human peripheral blood. FACS analysis showed that the incorporation of fluorescent BMPP into white blood cells was dose-dependent. Fluorescence intensities of cells incorporating fluorescent BMPP were attenuated after incubation in non-fluorescent BMPP medium, suggesting that these cells could export the probe. Neutrophils from a patient with primary triglyceride deposit cardiomyovasculopathy, a rare type of triglyceride (TG) metabolism disorders, showed lower BMPP export and was ameliorated after treatment with tricaprin. These results suggest that fluorescent BMPP could be imported to and exported from cells through the same mechanism as 123 I-BMIPP, reflecting the mechanism that occurs for LCFAs during TG metabolism. This study shows that fluorescent BMPP has the potential to be used as a probe for the diagnosis of TG metabolic diseases ex vivo .
2024-11-12 | Abstract 4139747: Inhibition of Acetyl -CoA Carboxylase 2 (ACC2) enhances fatty acid oxidation and improves cardiac function and survival in a severe model of heart failure
Heart failure (HF) is characterized by disordered energy metabolism including impaired mitochondrial oxidation and altered energy substrate preference. In triglyceride (TG) deposit cardiomyovasculopathy (TGCV; ORPHA code 565612), a rare form of HF characterized by impaired fatty acid oxidation (FAO), massive TG accumulation occurs in cardiac muscle and vasculature due to deficiency of adipose triglyceride lipase (ATGL). Since acetyl-CoA carboxylase 2 (ACC2) regulates fatty acid transport into mitochondria for oxidation, we hypothesized that genetic deletion or pharmacologic inhibition of ACC2 may improve cardiac function in the Atgl knockout (KO) mouse model of TGCV. Relative to Atgl KO mice, Atgl/Acc2 double KO mice had reduced cardiac TG accumulation and fibrosis, and significant improvements in cardiac function by echocardiography, locomotor activity, and survival (log-rank p <0.0001). These findings were recapitulated by treatment of Atgl KO mice with TLC-3595, a highly selective, systemic, small molecule ACC2 inhibitor in development for type 2 diabetes ( Figure ). After a single dose of TLC-3595 to Atgl KO mice, dose-dependent reductions in cardiac malonyl-CoA levels and TG content were observed. Further, in a detailed time-course echocardiographic analysis, Atgl KO mice had reduced left ventricular ejection fraction and evidence of cardiac remodeling which was ameliorated by TLC-3595 treatment. Metabolomic profiling of cardiac tissue revealed ACC2-specific changes, including reduced malonyl-CoA and increased acylcarnitines, consistent with increased FAO with TLC-3595 treatment. Moreover, levels of TCA cycle metabolites and acetylcarnitine were reduced in Atgl KO mice but increased with ACC2 deletion or TLC-3595. In summary, ACC2 deletion or pharmacologic inhibition restored cardiac energy metabolism towards increased FAO in Atgl KO mice, resulting in improved cardiac function and survival. These findings support the therapeutic targeting of ACC2, including with the selective small molecule ACC2 inhibitor TLC-3595, for the treatment of patients with HF associated with FAO deficiency.
2024-10-01 | Improvement of myocardial lipolysis in iodine-123-beta-methyl-P-iodophenyl-pentadecanoic acid scintigraphy in patients with idiopathic triglyceride deposit cardiomyovasculopathy treated with Tricaprin
Abstract Background Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare intractable cardiovascular disorder (Orphanet ORPHAcode: 565612) in which defective intracellular lipolysis results in heart failure and coronary artery disease. Myocardial scintigraphy with iodine-123-β-methyl-P-iodophenyl-pentadecanoic acid (BMIPP) is useful for evaluating myocardial TG metabolism and its washout rate (WR) reflects myocardial lipolysis. A decreased WR (<10%) of BMIPP is one of the diagnostic criteria for TGCV. CNT-01, the active ingredient of which is tricaprin, a medium-chain triglyceride, has the potential to facilitate myocardial lipolysis in a mouse model. However, the effects of CNT-01 (tricaprin) on BMIPP scintigraphy in patients with TGCV remain unclear. Purpose To evaluate the effects of CNT-01 on BMIPP-WR in patients with TGCV. Methods An investigator-initiated, randomized, double-blind exploratory trial (Phase IIa) was conducted. Ten patients with idiopathic TGCV in our hospital were enrolled and orally administered 1.5 g/day of CNT-01 or placebo for 8 weeks. The endpoint was the delta WR on BMIPP scintigraphy. All the participants underwent BMIPP scintigraphy after overnight fasting. Following the protocol recommended by the Japanese Society of Nuclear Cardiology, 111 MBq of BMIPP was intravenously injected at rest after fasting for ≥ 12 h. Early and delayed images were obtained after 20 and 180–210 min, respectively. BMIPP scintigraphy at baseline and 8-week was performed using the same SPECT apparatus. WR is defined as the ratio of the difference between the counts in the early image and time-decay-corrected delayed image divided by the former. We used a recently proposed algorithm for calculating the WR based on the total count and analyzed the WRs (Ann Nucl Cardiol. 2023;9(1):19-25). Results A total of 5 patients were assigned to placebo and 5 patients were assigned to CNT-01. During the protocol, delta BMIPP-WRs were -6.18 ± 4.43 and 5.44 ± 2.57 % (95% confidence intervals, -12.33 to -0.03 and 1.88 to 9.00) in the placebo and CNT-01 groups, respectively. The baseline-adjusted difference in delta BMIPP-WR between the two groups was significant (p=0.005) (Picture). No significant changes were observed in clinical parameters. Conclusion This study demonstrated that CNT-01 improved myocardial lipolysis in patients with TGCV as measured by BMIPP scintigraphy.
gene therapies
2025-08-01 | Abstract Wed022: BSCL2/Seipin Deletion Rescues ATGL-deficiency-induced Lethal Lipotoxic Cardiomyopathy via Modulating Cardiac Lipid Droplet Proteome
Imbalances in triglyceride (TG) catabolism are closely associated with cardiac lipid deposition and contractile dysfunction, as observed in patients with primary triglyceride deposit cardiomyovasculopathy (TGCV) due to adipose triglyceride lipase (ATGL) deficiency. BSCL2/Seipin is a highly conserved protein in the endoplasmic reticulum that plays a key role in lipid droplet (LD) biogenesis and TG metabolism. We previously reported that deleting BSCL2 in the heart increased myocardial ATGL expression and decreased cardiac steatosis. However, the relationship between BSCL2 and ATGL in the heart still needs further investigation. In this study, we unexpectedly found that both global and cardiac-specific deletion of BSCL2 completely alleviated lethal lipotoxic cardiomyopathy in the genetic TGCV model ( Atgl −/− mice and mice with cardiac-specific deletion of Atgl , referred to as A cKO ) by significantly reducing cardiac TG deposits, eliminating cardiac hypertrophy, and restoring cardiac contractility. Transcriptomic analyses revealed elevated inflammation, oxidative stress, and fibrosis in Atgl −/− hearts, which were dramatically attenuated by BSCL2 deletion. Conversely, the severely impaired cardiac metabolic functions, muscle contraction, and ion transport in Atgl −/− hearts were remarkably improved by BSCL2 deletion. Notably, the markedly downregulated Pgc1 / Ppara and fatty acid oxidation genes in Atgl -deficient hearts were restored by BSCL2 deletion. Further deletion of Pparα reverted Atgl −/− Bscl2 −/− hearts to lethal lipotoxic cardiomyopathy, indicating its crucial role in the rescue effects mediated by BSCL2 deletion. To identify the pathways that activate PPARα in the absence of ATGL and BSCL2, we conducted quantitative myocardial LD proteomics and discovered distinct LD proteomes characterized by an increased targeting of several neutral lipid hydrolases including hormone sensitive lipase (HSL) to the LDs in hearts with cardiac-specific deletions of both Atgl and Bscl2 compared to A cKO hearts. These findings suggest cardiac BSCL2 autonomously regulates ATGL-independent neutral lipid metabolism essential for cardiac function by mobilizing the LD proteome. In conclusion, our study reveals novel mechanistic insights into the role of BSCL2 in the LD proteome and offers new therapeutic strategies for treating lethal triglyceride deposit cardiomyopathy.
2023-11-07 | Abstract 14505: BSCL2/Seipin Deletion Rescues ATGL-Deficiency-Induced Lethal Lipotoxic Cardiomyopathy
Imbalances in triglyceride (TG) catabolism are associated with cardiac lipid deposition and contractile dysfunction, as manifested in patients with primary triglyceride deposit cardiomyovasculopathy (TGCV) caused by adipose triglyceride lipase (ATGL) deficiency. BSCL2/Seipin is a highly conserved endoplasmic reticulum protein widely implicated in lipid droplet biogenesis and TG metabolism. We previously reported that global Bscl2 –/– mice and mice with cardiac-specific deletion of Bscl2 manifest higher myocardial ATGL expression and develop mild cardiomyopathy with reduced cardiac steatosis. However, the interplay between BSCL2 and ATGL in hearts remains to be further interrogated. In this study, we surprisingly discovered that global BSCL2 deletion completely rescued the lethal lipotoxic cardiomyopathy in the genetic ATGL-deficient TGCV model ( Atgl –/– mice) by drastically reducing cardiac TG deposits, abolishing cardiac hypertrophy, and restoring cardiac contractility. Transcriptomic analyses identified the elevated inflammatory, oxidative stress, and extracellular matrix pathways in Atgl –/– hearts, which were dramatically ameliorated by BSCL2 deletion. Conversely, the severely suppressed cardiac metabolic functions, muscle contraction, and ion transport pathways in Atgl –/– hearts were also normalized by BSCL2 deletion. Heatmap data further revealed that the mRNA levels of Pgc1/Ppara and fatty acid oxidation (FAO) genes were not altered in Bscl2 –/– hearts but were severely repressed in Atgl –/– hearts due to defective TG lipolysis. However, their expressions in Atgl –/– Bscl2 –/– hearts were restored to similar levels as wild-type and Bscl2 –/– hearts. RT-PCR analyses further confirmed such changes. Notably, cardiac-specific deletion of BSCL2 rescues lethal cardiomyopathy in mice with cardiac-specific deletion of ATGL. These data suggest that cardiac BSCL2 cell-autonomously regulates ATGL-independent TG hydrolysis and FAO pathways essential for cardiac function. Our study highlights the presence of BSCL2-mediated ATGL-independent pathways that regulate cardiac TG metabolism and provide novel therapeutic approaches to treat ATGL-deficiency-associated lethal cardiomyopathy.
2021-10-26 | Cardiac-specific CGI-58 deficiency activates the ER stress pathway to promote heart failure in mice
Excess myocardial triacylglycerol accumulation (i.e., cardiac steatosis) impairs heart function, suggesting that enzymes promoting triacylglycerol metabolism exert essential regulatory effects on heart function. Comparative gene identification 58 (CGI-58) is a key enzyme that promotes the hydrolysis of triglycerides by activating adipose triglyceride lipase and plays a protective role in maintaining heart function. In this study, the effects of CGI-58 on heart function and the underlying mechanism were investigated using cardiac-specific CGI58-knockout mice (CGI-58cko mice). Echocardiography and pathological staining were performed to detect changes in the structure and function of the heart. Proteomic profiling, immunofluorescent staining, western blotting, and real-time PCR were used to evaluate molecular changes. In CGI-58cko mice, we detected cardiac hypertrophic remodeling and heart failure associated with excessive cardiac lipid accumulation, ROS production, and decreased expression of regulators of fatty acid metabolism. These changes were markedly attenuated in CGI-58cko mice injected with rAAV9-CGI58. A quantitative proteomics analysis revealed significant increases in the expression of ER stress-related proteins and decreases in proteins related to fatty acid and amino acid metabolism in the hearts of CGI-58cko mice. Furthermore, the inhibition of ER stress by the inhibitor 4-PBA improved mitochondrial dysfunction, reduced oxidative stress, and reversed cardiac remodeling and dysfunction in cultured cardiomyocytes or in CGI-58cko mice. Our results suggested that CGI-58 is essential for the maintenance of heart function by reducing lipid accumulation and ER stress in cardiomyocytes, providing a new therapeutic target for cardiac steatosis and dysfunction.
proteins
2024-02-04 | Mfn2/Hsc70 Complex Mediates the Formation of Mitochondria‐Lipid Droplets Membrane Contact and Regulates Myocardial Lipid Metabolism
Abstract The heart primarily derives its energy through lipid oxidation. In cardiomyocytes, lipids are stored in lipid droplets (LDs) and are utilized in mitochondria, although the structural and functional connections between these two organelles remain largely unknown. In this study, visible evidence have presented indicating that a complex is formed at the mitochondria‐LD membrane contact (MLC) site, involving mitochondrion‐localized Mfn2 and LD‐localized Hsc70. This complex serves to tether mitochondria to LDs, facilitating the transfer of fatty acids (FAs) from LDs to mitochondria for β‐oxidation. Reduction of Mfn2 induced by lipid overload inhibits MLC, hinders FA transfer, and results in lipid accumulation. Restoring Mfn2 reinstates MLC, alleviating myocardial lipotoxicity under lipid overload conditions both in‐vivo and in‐vitro. Additionally, prolonged lipid overload induces Mfn2 degradation through the ubiquitin‐proteasome pathway, following Mfn2 acetylation at the K243 site. This leads to the transition from adaptive lipid utilization to maladaptive lipotoxicity. The experimental findings are supported by clinical data from patients with obesity and age‐matched non‐obese individuals. These translational results make a significant contribution to the molecular understanding of MLC in the heart, and offer new insights into its role in myocardial lipotoxicity.
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