Acetyl‐coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double‐blind, crossover study

Abstract

NDI‐010976, an allosteric inhibitor of acetyl‐coenzyme A carboxylases (ACC) ACC1 and ACC2, reduces hepatic de novo lipogenesis (DNL) and favorably affects steatosis, inflammation, and fibrosis in animal models of fatty liver disease. This study was a randomized, double‐blind, placebo‐controlled, crossover trial evaluating the pharmacodynamic effects of a single oral dose of NDI‐010976 on hepatic DNL in overweight and/or obese but otherwise healthy adult male subjects. Subjects were randomized to receive either NDI‐010976 (20, 50, or 200 mg) or matching placebo in period 1, followed by the alternate treatment in period 2; and hepatic lipogenesis was stimulated with oral fructose administration. Fractional DNL was quantified by infusing a stable isotope tracer, [1‐13C]acetate, and monitoring 13C incorporation into palmitate of circulating very low‐density lipoprotein triglyceride. Single‐dose administration of NDI‐010976 was well tolerated at doses up to and including 200 mg. Fructose administration over a 10‐hour period stimulated hepatic fractional DNL an average of 30.9 ± 6.7% (mean ± standard deviation) above fasting DNL values in placebo‐treated subjects. Subjects administered single doses of NDI‐010976 at 20, 50, or 200 mg had significant inhibition of DNL compared to placebo (mean inhibition relative to placebo was 70%, 85%, and 104%, respectively). An inverse relationship between fractional DNL and NDI‐010976 exposure was observed with >90% inhibition of fractional DNL associated with plasma concentrations of NDI‐010976 >4 ng/mL. Conclusion: ACC inhibition with a single dose of NDI‐010976 is well tolerated and results in a profound dose‐dependent inhibition of hepatic DNL in overweight adult male subjects. Therefore, NDI‐010976 could contribute considerable value to the treatment algorithm of metabolic disorders characterized by dysregulated fatty acid metabolism, including nonalcoholic steatohepatitis. (Hepatology 2017;66:324–334).

WITHDRAWN: Ginkgolide B reduces hepatic lipid accumulation and ameliorates nonalcoholic fatty liver disease in high-fat diet–induced obese mice

“…Treated hepatocytes did not take up excess free fatty acids, and liver cells did not activate transcription factors involved in lipid synthesis to synthesize more TGs; the result would be expected to be reduced hepatocyte lipid accumulation [34]. Interestingly, we also found that ginkgolide B did not decrease TG levels in serum.…”

Activity and structure of human acetyl‐CoA carboxylase targeted by a specific inhibitor

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We have studied a series of human acetyl-CoA carboxylase (ACC) 1 and ACC2 proteins with deletions and/or Ser to Ala substitutions of the known phosphorylation sites. A number of inhibitors of human ACCs have been studied [10,[12][13][14][15][16][17][18][19]. Our results are consistent with AMPK phosphorylation of Ser 29 , Ser 80 , Ser 1,201 , and Ser 1,216 .

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“…Such key roles of ACCs in fatty acid metabolism make them potential drug target [1][2][3][4][5][6][7][8][9][10][11]. In vitro dephosphorylation/phosphorylation experiments reveal a substantial level of phosphorylation of human ACCs produced in insect cells.…”

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

“…(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).…”