Down-regulation of hepatic CLOCK by PPARα is involved in inhibition of NAFLD

Abstract

This work aimed to investigate the role of nuclear factor peroxisome proliferator-activated receptor α (PPARα) in modification of circadian clock and their relevance to development of nonalcoholic fatty liver disease (NAFLD). Both male wild-type (WT) and Pparα-null (KO) mice treated with high-fat diet (HFD) were used to explore the effect of PPARα and lipid diet on the circadian rhythm. WT, KO, and PPARα-humanized (hPPARα) mice were treated with PPARα agonist fenofibrate to reveal the hPPARα dependence of circadian locomotor output cycles kaput (CLOCK) down-regulation. The mouse model and hepatocyte experiments were designed to verify the action of PPARα in down-regulating CLOCK and lipid accumulation in vivo and in vitro. Strongest NAFLD developed in mice fed 45%HFD, and it was inhibited in WT mice. The activity rhythm of WT mice was found to be different from that of the KO mice on normal diet and HFD. The core circadian factor CLOCK was down-regulated by HFD in both WT and KO mice in the liver, not in the hypothalamus. More interestingly, hepatic CLOCK was down-regulated by basal PPARα and activated PPARα in dose dependence of fenofibrate. Accordingly, CLOCK down-regulation dependent of PPARα activity was involved in inhibition of lipid metabolism in hepatocytes. Down-regulation of hepatic CLOCK by basal PPARα contributes to tolerance against development of NAFLD. Inhibition of CLOCK by activated PPARα is involved in inhibition of NAFLD by PPARα agonists. KEY MESSAGES: • PPARα inhibited NAFLD development induced by HFD. • PPARα mediated modifications of circadian rhythm and the hepatic circadian factor CLOCK in NAFLD models. • Down-regulation of hepatic CLOCK by basal PPARα contributed to tolerance against development of NAFLD. • Inhibition of CLOCK by activated PPARα was involved in therapeutic actions against fatty liver diseases by PPARα agonists.

Keywords: CLOCK; Circadian rhythm; Lipid accumulation; NAFLD; PPARα.