GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease

Loomba, Rohit; Kayali, Zeid; Noureddin, Mazen; Ruane, Peter; Lawitz, Eric; Bennett, Michael; Wang, Lulu; Harting, Eliza; Tarrant, Jacqueline M.; Mccolgan, B.; Chung, Chuhan; Ray, Adrian S.; Subramanian, G. Mani; Myers, Robert P.; Middleton, Michael S.; Lai, Michelle; Charlton, Michael; Harrison, Stephen A.

doi:10.1053/j.gastro.2018.07.027

Cited by 249 publications

(244 citation statements)

References 38 publications

Supporting

Mentioning

229

Contrasting

Unclassified

Order By: Relevance

“…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%

“…Multiple studies support pharmacologic inhibition of ACC1 and ACC2 for the treatment of NAFLD through simultaneous inhibition of DNL and stimulation of fatty acid oxidation . In particular, two clinical trials of the liver‐directed ACC inhibitor GS‐0976 found statistically significant decreases in hepatic steatosis and the marker of fibrosis tissue inhibitor of metalloproteinase 1 in patients with NASH and fibrosis . However, the effect of ACC inhibition on hepatic mitochondrial oxidation, gluconeogenesis, hepatic glucose production, and ketogenesis in vivo has not yet been explored.…”

Section: Discussionmentioning

confidence: 99%

“…(11) In addition, a liverdirected allosteric inhibitor of ACC1 and ACC2 (GS-0976) has been shown to improve hepatic steatosis and markers of liver injury in patients with NASH and to reduce hepatic steatosis and dyslipidemia in rodent models of obesity. (12)(13)(14) Despite this, the effect of liver-directed ACC inhibition on hepatic mitochondrial oxidation, anaplerosis, and ketogenesis in vivo is unknown. Here, we performed a comprehensive set of metabolic flux analyses to assess these parameters in both chow-fed rats and rat models of diet-induced obesity (DIO).…”

Section: See Editorial On Page 2062mentioning

confidence: 99%

“…Specifically, we demonstrated that reducing hepatic expression of ACC1 and ACC2 using antisense oligonucleotides results in marked reductions in hypertriglyceridemia, hepatic triglyceride content, and reversal of hepatic insulin resistance in a high‐fat‐fed rodent model of NAFLD and hepatic insulin resistance . In addition, a liver‐directed allosteric inhibitor of ACC1 and ACC2 (GS‐0976) has been shown to improve hepatic steatosis and markers of liver injury in patients with NASH and to reduce hepatic steatosis and dyslipidemia in rodent models of obesity . Despite this, the effect of liver‐directed ACC inhibition on hepatic mitochondrial oxidation, anaplerosis, and ketogenesis in vivo is unknown.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2018

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: See Editorial On Page 2062mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…ACC inhibitors decrease hepatic triglyceride contents, which is attributable to anticipated effects of reducing de novo lipogenesis and increasing rates of fatty acid oxidation. These findings have now been validated in a phase II trial of a liver‐targeted, allosteric inhibitor of ACC1 and ACC2, which demonstrated reduced hepatic steatosis and improved markers of fibrosis …”

mentioning

confidence: 83%