Acetyl-CoA Carboxylase Inhibition Improves Multiple Dimensions of NASH Pathogenesis in Model Systems

Abstract

The pathogenesis of nonalcoholic steatohepatitis is multifactorial, involving steatosis, lipotoxicity, hepatic inflammation, and fibrosis. The present studies show that acetyl-CoA carboxylase inhibition produces direct improvements in hepatic steatosis, inflammation, and fibrosis in both primary human cell systems and rodent nonalcoholic fatty liver disease/nonalcoholic steatohepatitis models.

Acetyl-CoA Carboxylase Inhibition as a Therapeutic Tool in the Battle Against NASH: Hitting More Than Just One Mechanism?

“…In line with previous observations made through use of other ACC inhibitors, 4 , 5 PF-05221304 diminished de novo lipogenesis, both in isolated primary human cells and in Western diet–fed rats. 6 However, in contrast with previous studies that had reported an elevation in circulating triglyceride levels, 4 , 5 no significant changes in body weight, fasting glucose, triglyceride, and cholesterol levels were observed. Interestingly, although dose-dependent reductions in hepatic triglyceride levels were identified in the PF-05221304-treated Western diet model, no effects on the extent of hepatic steatosis were observed when administrating the drug to diethylnitrosamine (DEN) and choline deficient and high-fat diet (CDAHFD) rat models.…”

“…Interestingly, although dose-dependent reductions in hepatic triglyceride levels were identified in the PF-05221304-treated Western diet model, no effects on the extent of hepatic steatosis were observed when administrating the drug to diethylnitrosamine (DEN) and choline deficient and high-fat diet (CDAHFD) rat models. 6 Because of the known association of increasing levels of infiltrating inflammatory cells during the NASH pathology, and the recent association of an elevated ratio of Th17-inflammatory over Treg-cells to NASH progression, 7 Ross et al 6 decided to also investigate the effect of PF-05221304 on the inflammatory outcome. Interestingly, they found that the drug suppresses the polarization of T cells toward the proinflammatory Th17 T cells, but not the anti-inflammatory Treg cells.…”

“…Additionally, the administration of PF-05221304 to the DEN and CDAHFD rodent models led to an overall reduction in hepatic inflammation. 6 Previous reports concerning the effects of ACC inhibitors on fibrogenesis were inconsistent. Although most studies did not describe fibrosis-alternating effects, or even observed negative results, 5 a recent study reported direct inhibition of hepatic stellate cell (HSC)-activation and fibrosis outcome in a DEN and CDAHFD rat model using the ACC inhibitor firsocostat.…”

“…8 In line with these observations, Ross et al 6 also find, using the same rodent models of liver disease, reduced expression of the fibrogenic markers aSMA and Col1a1 following treatment with PF-05221304. 6 Both studies suggest such antifibrotic effects to be caused by direct (inhibition of de novo lipogenesis in the HSC) and indirect (less lipotoxicity) mechanisms.…”

“…In this issue of Cellular and Molecular Gastroenterology and Hepatology , Ross et al 6 explore the effects of PF-05221304, a dual ACC1/2-inhibitor, in rodent models of NASH, and in vitro studies using primary human liver cells. In line with previous observations made through use of other ACC inhibitors, 4 , 5 PF-05221304 diminished de novo lipogenesis, both in isolated primary human cells and in Western diet–fed rats.…”