Acetyl-CoA carboxylase (ACC) inhibitor GS-0976 leads to suppression of hepatic de novo lipogenesis and significant improvements in MRI-PDFF, MRE, and markers of fibrosis after 12 weeks of therapy in patients with NASH

Lawitz, Eric; Poordad, Fred; Coste, Aurélien; Loo, Nicole; Djedjos, C. Stephen; Mccolgan, B.; Jia, Changku; Xu, Renjie; Myers, Robert P.; Subramanian, G. Mani; McHutchison, John G.; Middleton, Michael S.; Sirlin, Claude B.; Nyangau, Edna; Fitch, Mark; Li, K.; Hellerstein, Marc K.

doi:10.1016/s0168-8278(17)30328-8

Cited by 26 publications

(31 citation statements)

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“…Elafibranor, a dual peroxisome proliferator‐activated receptor‐α/δ agonist, failed to meet the predefined endpoint (i.e., resolution of NASH without fibrosis worsening) in the intention‐to‐treat population in a phase II trial; however, a post‐hoc analysis accounting for baseline patient heterogeneity and severity of disease demonstrated a dose‐dependent improvement in liver histology (http://ClinicalTrials.gov number NCT01694849). Interestingly, in a recently reported initial proof‐of‐concept trial in NASH patients, oral treatment with liver‐targeted, selective inhibitor of ACC GS‐0976 was shown to significantly improve liver steatosis as well as circulating biomarkers of liver fibrosis and cell death . These data suggest that the repression of hepatic ACC levels by Stk25 ASOs, which we observed in this study, may constitute a key mechanism for the effect of Stk25 ASOs not only on reducing liver steatosis but also for suppressing fibrosis and hepatocellular damage.…”

Section: Discussionsupporting

confidence: 70%

Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice

Nuñez-Durán

Aghajan

Amrutkar

et al. 2017

Hepatology Communications

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Nonalcoholic fatty liver disease (NAFLD) contributes to the pathogenesis of type 2 diabetes and cardiovascular disease, and patients with nonalcoholic steatohepatitis (NASH) are also at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. To date, no specific therapy exists for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the twenty‐first century. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of energy homeostasis and NAFLD progression. Here, we investigated the effect of antisense oligonucleotides (ASOs) targeting Stk25 on the metabolic and molecular phenotype of mice after chronic exposure to dietary lipids. We found that Stk25 ASOs efficiently reversed high‐fat diet‐induced systemic hyperglycemia and hyperinsulinemia, improved whole‐body glucose tolerance and insulin sensitivity, and ameliorated liver steatosis, inflammatory infiltration, apoptosis, hepatic stellate cell activation, and nutritional fibrosis in obese mice. Moreover, Stk25 ASOs suppressed the abundance of liver acetyl‐coenzyme A carboxylase (ACC) protein, a key regulator of both lipid oxidation and synthesis, revealing the likely mechanism underlying repression of hepatic fat accumulation by ASO treatment. We also found that STK25 protein levels correlate significantly and positively with NASH development in human liver biopsies, and several common nonlinked single‐nucleotide polymorphisms in the human STK25 gene are associated with altered liver fat, supporting a critical role of STK25 in the pathogenesis of NAFLD in humans. Conclusion: Preclinical validation for the metabolic benefit of pharmacologically inhibiting STK25 in the context of obesity is provided. Therapeutic intervention aimed at reducing STK25 function may provide a new strategy for the treatment of patients with NAFLD, type 2 diabetes, and related complex metabolic diseases. (Hepatology Communications 2018;2:69–83)

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Section: Discussionsupporting

confidence: 70%

Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice

Nuñez-Durán

Aghajan

Amrutkar

et al. 2017

Hepatology Communications

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“…This increase was independent of changes in plasma insulin concentrations and likely reflects increases in hepatic acetyl‐CoA content, which has been shown to increase hepatic gluconeogenesis through allosteric activation of pyruvate carboxylase . The opposing effects of increased hepatic insulin sensitivity and increased HGP may explain the lack of an effect on fasting plasma glucose observed in this study and in patients with NASH treated for 12 weeks with GS‐0976 . The net effect of these changes on long‐term glycemic control in patients with metabolic dysfunction requires further clinical investigation.…”

Section: Discussionmentioning

confidence: 66%

Acetyl‐CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents

et al. 2018

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Pharmacologic inhibition of acetyl-CoA carboxylase (ACC) enzymes, ACC1 and ACC2, offers an attractive therapeutic strategy for nonalcoholic fatty liver disease (NAFLD) through simultaneous inhibition of fatty acid synthesis and stimulation of fatty acid oxidation. However, the effects of ACC inhibition on hepatic mitochondrial oxidation, anaplerosis, and ketogenesis in vivo are unknown. Here, we evaluated the effect of a liver-directed allosteric inhibitor of ACC1 and ACC2 (Compound 1) on these parameters, as well as glucose and lipid metabolism, in control and diet-induced rodent models of NAFLD. Oral administration of Compound 1 preferentially inhibited ACC enzymatic activity in the liver, reduced hepatic malonyl-CoA levels, and enhanced hepatic ketogenesis by 50%. Furthermore, administration for 6 days to high-fructose-fed rats resulted in a 20% reduction in hepatic de novo lipogenesis. Importantly, long-term treatment (21 days) significantly reduced high-fat sucrose diet-induced hepatic steatosis, protein kinase C epsilon activation, and hepatic insulin resistance. ACCi treatment was associated with a significant increase in plasma triglycerides (approximately 30% to 130%, depending on the length of fasting). ACCi-mediated hypertriglyceridemia could be attributed to approximately a 15% increase in hepatic very low-density lipoprotein production and approximately a 20% reduction in triglyceride clearance by lipoprotein lipase (P ≤ 0.05). At the molecular level, these changes were associated with increases in liver X receptor/sterol response element-binding protein-1 and decreases in peroxisome proliferator-activated receptor-α target activation and could be reversed with fenofibrate co-treatment in a high-fat diet mouse model. Conclusion: Collectively, these studies warrant further investigation into the therapeutic utility of liver-directed ACC inhibition for the treatment of NAFLD and hepatic insulin resistance.

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“…Additionally, another trial for treatment of NASH focuses on an inhibitor of acyl co‐A carboxylase (ACC), a rate‐limiting step in de novo lipogenesis. In a very small open label study, an ACC inhibitor showed reduction in alanine aminotransferase, elastometry and MRI PDFF quantification of liver fat …”

Section: Emerging Therapy For Nash: Nonantifibrotic and Antifibrotic mentioning

confidence: 99%

Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

et al. 2018

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Acetyl-CoA carboxylase (ACC) inhibitor GS-0976 leads to suppression of hepatic de novo lipogenesis and significant improvements in MRI-PDFF, MRE, and markers of fibrosis after 12 weeks of therapy in patients with NASH

Cited by 26 publications

References 0 publications

Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice

Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice

Acetyl‐CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents

Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

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