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

Area of Science:

• Hepatology
• Pharmacology
• Metabolic Diseases

Background:

• Nonalcoholic steatohepatitis (NASH) pathogenesis involves disordered metabolism, steatosis, hepatic inflammation, and fibrosis.
• Acetyl-CoA carboxylase (ACC) regulates de novo lipogenesis (DNL) and fatty acid oxidation, key processes implicated in NASH.
• PF-05221304 is an orally bioavailable, liver-directed ACC1/2 inhibitor designed to target NASH pathology.

Purpose of the Study:

• To evaluate the effects of PF-05221304 on NASH pathogenic factors.
• To assess the drug's impact on lipid metabolism, steatosis, inflammation, and fibrogenesis in experimental systems.

Main Methods:

• Investigated PF-05221304 in primary human-derived in vitro systems and in vivo rodent models.
• Assessed effects on lipid metabolism, steatosis, inflammation, and fibrogenesis.
• Utilized Western diet-fed rats, diethylnitrosamine-induced liver injury model, and choline-deficient, high-fat-fed rat model.

Main Results:

• PF-05221304 inhibited DNL, stimulated fatty acid oxidation, and reduced triglycerides in human hepatocytes.
• In vivo, the inhibitor reduced DNL and steatosis in rats, and suppressed T cell polarization and stellate cell activation.
• PF-05221304 decreased markers of inflammation and fibrosis in rodent models of liver injury.

Conclusions:

• The liver-directed dual ACC1/ACC2 inhibitor PF-05221304 demonstrated direct improvement of NASH pathogenic factors.
• The drug effectively addressed steatosis, inflammation, and fibrosis in both human in vitro systems and rat models.
• PF-05221304 shows potential as a therapeutic agent for nonalcoholic fatty liver disease and NASH.