Hepatic ACLY deficiency and bempedoic acid drive divergent responses to dietary lipid

ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in non-alcoholic fatty liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol lowering drug bempedoic acid (BPA), which has been shown to improve steatosis in mice. However, the acetyl-CoA synthetase ACSS2 can compensate for ACLY deficiency to support DNL, potentially complicating the targeting of ACLY. We show that hepatic loss of both ACLY and ACSS2 reduces DNL. Nevertheless, even when ACSS2 is suppressed by dietary or genetic means, we find that steatosis is counterintuitively exacerbated with hepatic ACLY deficiency in mice fed a Western diet (WD), linked to reduced expression of PPARa target genes controlling fatty acid oxidation. Conversely, BPA treatment increased fat catabolism and ameliorated WD-mediated lipid accumulation in both WT and liver ACLY knockout mice. Thus, hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation, and BPA improves steatosis independent of ACLY.