Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis

Lawitz, Eric; Coste, Angie; Poordad, Fred; Alkhouri, Naim; Loo, Nicole; Mccolgan, B.; Tarrant, Jacqueline M.; Nguyen, Tuan; Han, Lina; Chung, Chuhan; Ray, Adrian S.; McHutchison, John G.; Subramanian, G. Mani; Myers, Robert P.; Middleton, Michael S.; Sirlin, Claude B.; Loomba, Rohit; Nyangau, Edna; Fitch, Mark; Li, Kelvin; Hellerstein, Marc K.

doi:10.1016/j.cgh.2018.04.042

Cited by 174 publications

(161 citation statements)

References 27 publications

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“…Additional work is needed to delineate precisely how hepatocyte actions of Plin2 influence HSC activation and fibrosis. However, our findings are consistent with the reported communication between hepatocytes and HSCs (Marrone et al 2016) and evidence linking hepatocyte DNL activation to hepatic fibrosis in NASH patients (Pinkosky et al 2017;Lawitz et al 2018;Loomba et al 2018).…”

Section: Discussionsupporting

confidence: 93%

Perilipin‐2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra‐hepatocyte actions

Orlicky

Libby

Bales

et al. 2019

The Journal of Physiology

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Key points Wild‐type mice and mice with hepatocyte‐specific or whole‐body deletions of perilipin‐2 (Plin2) were used to define hepatocyte and extra‐hepatocyte effects of altered cellular lipid storage on obesity and non‐alcoholic fatty liver disease (NAFLD) pathophysiology in a Western‐diet (WD) model of these disorders. Extra‐hepatocyte actions of Plin2 are responsible for obesity, adipose inflammation and glucose clearance abnormalities in WD‐fed mice. Hepatocyte and extra‐hepatic actions of Plin2 mediate fatty liver formation in WD‐fed mice through distinct mechanisms. Hepatocyte‐specific actions of Plin2 are primary mediators of immune cell infiltration and fibrotic injury in livers of obese mice. Abstract Non‐alcoholic fatty liver disease (NAFLD) is an obesity‐ and insulin resistance‐related metabolic disorder with progressive pathology. Perilipin‐2 (Plin2), a ubiquitously expressed cytoplasmic lipid droplet scaffolding protein, is hypothesized to contribute to NAFLD in humans and rodent models through effects on cellular lipid metabolism. In this study, we delineate hepatocyte‐specific and extra‐hepatocyte Plin2 mechanisms regulating the effects of obesity and insulin resistance on NAFLD pathophysiology in mice fed an obesogenic Western‐style diet (WD). Total Plin2 deletion (Plin2‐Null) fully protected WD‐fed mice from obesity, insulin resistance, adipose inflammation, steatohepatitis (NASH) and liver fibrosis found in WT animals. Hepatocyte‐specific Plin2 deletion (Plin2‐HepKO) largely protected against NASH and fibrosis and partially protected against steatosis in WD‐fed animals, but it did not protect against obesity, insulin resistance, or adipose inflammation. Significantly, total or hepatocyte‐specific Plin2 deletion impaired WD‐induced monocyte recruitment and pro‐inflammatory macrophage polarization found in livers of WT mice. Analyses of the molecular and cellular processes mediating steatosis, inflammation and fibrosis identified differences in total and hepatocyte‐specific actions of Plin2 on the mechanisms promoting NAFLD pathophysiology. Our results demonstrate that hepatocyte‐specific actions of Plin2 are central to the initiation and pathological progression of NAFLD in obese and insulin‐resistant mice through effects on immune cell recruitment and fibrogenesis. Conversely, extra‐hepatocyte Plin2 actions promote NAFLD pathophysiology through effects on obesity, inflammation and insulin resistance. Our findings provide new insight into hepatocyte and extra‐hepatocyte mechanisms underlying NAFLD development and progression.

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Section: Discussionsupporting

confidence: 93%

Perilipin‐2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra‐hepatocyte actions

Orlicky

Libby

Bales

et al. 2019

The Journal of Physiology

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“…The mechanism for the increase in serum triglycerides is thought to be a combination of increased very low-density lipoprotein synthesis and release by hepatocytes, and a reduction in triglyceride clearance caused by decreased lipoprotein lipase activity on endothelial cells. 5 In broad terms, this phase II study confirmed the efficacy findings of an earlier pilot study of GS-0976, 6 showing a >30% relative decrease in steatosis in 48% of patients on the high dose and 23% on the low dose, compared with 15% in the placebo group. Changes in liver stiffness as measured by magnetic resonance elastography were not different between the 3 groups, but there was indirect evidence of increased matrix degradation in the high-dose group based on reduction in serum tissue inhibitor of metalloproteinase 1 levels.…”

supporting

confidence: 83%

Acetyl-Coenzyme A carboxylase inhibition Delivers, as Anticipated, for Patients With Nonalcoholic Steatohepatitis

Mehal

2018

Gastroenterology

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“…Small changes in other lipid levels were noted; this has been observed with other ACC inhibitors where VLDL, LDL‐C, and HDL‐C levels increased or HDL‐C slightly decreased with no significant associations between lipid changes and changes in glycemic parameters or body weight . However, lipid monitoring is warranted to assess any atherogenic risk.…”

Section: Discussionmentioning

confidence: 74%

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Liver‐Targeting Acetyl‐CoA Carboxylase Inhibitor (PF‐05221304): A Three‐Part Randomized Phase 1 Study

Bergman

Carvajal‐Gonzalez

Tarabar

et al. 2020

Clinical Pharm in Drug Dev

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PF-05221304 is a liver-targeted inhibitor of acetyl-CoA carboxylase, an enzyme that catalyzes the first committed step in de novo lipogenesis (DNL). This first-in-human study investigated safety/tolerability and pharmacokinetics of single and multiple ascending oral PF-05221304 doses, and fructose-stimulated DNL inhibition with repeated oral doses. Healthy subjects (n = 96) received single (1-240 mg) or repeated (2-200 mg daily) doses for 14 days or single 100-mg doses with and without food. PF-05221304 was well tolerated at all doses. Repeated PF-05221304 doses inhibited hepatic DNL in a dose-dependent manner, with near-complete inhibition seen at higher doses. With doses yielding ࣙ90% DNL inhibition, asymptomatic increases in fasting/postprandial serum triglyceride levels (ࣙ40 mg/day) and declines in platelet count (ࣙ60 mg/day) occurred; these were not observed at ࣘ80% DNL inhibition. Steady-state pharmacokinetics generally increased dose-proportionally, with a half-life of 14-18 hours and a minimal food effect on plasma exposure. The observed safety and tolerability, pharmacokinetics, and pharmacodynamics support the continued evaluation of PF-05221304 for the treatment of nonalcoholic steatohepatitis.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis

Cited by 174 publications

References 27 publications

Perilipin‐2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra‐hepatocyte actions

Perilipin‐2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra‐hepatocyte actions

Acetyl-Coenzyme A carboxylase inhibition Delivers, as Anticipated, for Patients With Nonalcoholic Steatohepatitis

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Liver‐Targeting Acetyl‐CoA Carboxylase Inhibitor (PF‐05221304): A Three‐Part Randomized Phase 1 Study

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