The character of nonalcoholic fatty liver disease (NAFLD) is the accumulation of fat (in excess of 5%) within the hepatocytes. The molecular etiology of NASH is complex, including disordered metabolism, hepatocyte injury, and progressive fibrosis. Increased rates of hepatic de novo lipogenesis (DNL) is a distinctive characteristic of NAFLD.
Altering the balance of hepatic triglyceride (TG) accumulation and removal by reducing fat production or promoting fat clearance are able to reduce steatosis.
Acetyl-CoA carboxylase (ACC) is a key enzyme regulating lipid metabolism, Additionally, it can catalyze the ATP-dependent condensation of acetyl-CoA with carbonate to produce malonyl-CoA.
ACC contains 2 isoforms: ACC1 and ACC2. ACC inhibition stimulates fatty acid oxidation. Besides, the inhibition also suppresses hepatic DNL and consequently reduces steatosis. What’s more, the suppression of DNL through ACC inhibition can reduce inflammation.
In this article, we will introduce an orally bioavailable, liver-directed, and dual ACC1 (and ACC2) inhibitor, PF-05221304.
The IC50 for rat ACC1, rat ACC2, human ACC1 and human ACC2 are 7.5 nM, 8.2 nM, 12.4 nM AND 8.7 nM, respectively. It is a substrate for organic anion transport polypeptides. Additionally, PF-05221304 inhibits hepatic de novo lipogenesis (DNL) with an IC50 of 61 nM in human hepatocytes (donor HH AA 508) in a concentration-dependent manner. Additionally, the inhibitor stimulates fatty acid oxidation and reduces triglyceride accumulation.
In male Wistar Han rats, pre-treatment with a choline-deficient and high-fat diet (CDAHFD) can reduce the expression of these genes (α-SMA, Col1A1, Col3A1, CCL2, and CCL11) in vivo. However, PF-05221304 significantly reduces the expression of these genes by 44%-61%. Furthermore, Chronic administration of PF-05221304 decreases hepatic inflammation and fibrosis in choline-deficient and high-fat diet-fed rats.
In conclusion, PF-05221304 is a liver-directed ACC1/2 inhibitor. PF-05221304 produces improvements in multiple dimensions of NASH pathogenesis in vivo. This inhibitor can be used for NASH research.