announced results from a Phase 2, randomized, placebo-controlled trial evaluating two doses of GS-0976, an oral, investigational inhibitor of
Acetyl-CoA carboxylase, in patients with nonalcoholic steatohepatitis.
A separate Phase 2 study is investigating treatment with GS-9674, the investigational apoptosis signal-regulating kinase 1 inhibitor selonsertib, and the investigational
acetyl-CoA carboxylase inhibitor GS-0976 alone or in combination, in patients with advanced fibrosis due to NASH.
Upstream regulators of de novo lipogenesis (i.e., carbohydrate response element-binding protein [ChREBP] and sterol regulatory element-binding protein 1c [SREBP-1c]) were measured by polymerase chain reaction and key lipogenic enzymes (
acetyl-CoA carboxylase [ACC], fatty acid synthase [FAS], and stearoyl-CoA desaturase-1 [SCD-1]) by Western blotting.
In addition, adiponectin inhibits gluconeogenesis by phosphorylating AMPK and
acetyl-CoA carboxylase (ACC) [11].
The study combines the apoptosis signal-regulating kinase 1 inhibitor selonsertib with either the
acetyl-CoA carboxylase inhibitor GS-0976 or the selective, non-steroidal Farnesoid X receptor agonist GS-9674.
Adipocyte RNA was analyzed for relative expression of DIO2, a gene associated with endocrine function (LEPTIN, ADIPOQ), mitochondrial function (cell death activator (CIDEA), ATP synthase (ATP5A), and carnitine palmitoyltransferase 1B (CPT1B)), fatty acid [beta]-oxidation (acetyl CoA dehydrogenase (ACADM)), fatty acid synthesis (
acetyl-CoA carboxylase (ACC2), fatty acid synthase (FASN), and diglyceride acyltransferase (DGAT)), adipocyte function (PPARgamma (PPAR[gamma])), innate immunity (NLRP3), and select proinflammatory or anti-inflammatory cytokines or chemoattractants (tumor necrosis factor alpha (TNF[alpha]), interleukin-1[beta] (IL-1[beta]), and plasminogen activator inhibitor-1 (PAI-1)).
AMPK activates energy-generating pathways by increasing fatty acid oxidation via phosphorylation of
acetyl-coA carboxylase 2 (ACC2) and glycolysis via activation of phosphofructo-2kinase (PFK) (Figure 1(a)).
Also in the liver, fructose induces mRNA expression from Glut-2, Glut-5, fatty acid synthase (FAS), and
acetyl-CoA carboxylase (ACC1) [29].
Acetyl-CoA carboxylase catalyzes the conversion of acetyl-CoA into malonyl-CoA, which constitutes the initial reaction in fatty acid biosynthesis [26].
United States-based Gilead Sciences has revealed results from a Phase two, randomised, placebo-controlled trial assessing two doses of GS-0976, an oral, investigational inhibitor of
Acetyl-CoA carboxylase intended for patients with non-alcoholic steatohepatitis (NASH), it was reported yesterday.
Lawitz, MD, reported the promising results of a "proof of concept" open-label study in which the safety and efficacy of 12 weeks' treatment with the oral
acetyl-CoA carboxylase (ACC) inhibitor, GS-0976, was examined in 10 patients with a clinical diagnosis of nonalcoholic fatty liver disease (NAFLD).