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 modi cation 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 clock. PPARα humanized (hPPARα) mice were treated with PPARα agonist feno brate to reveal the hPPARα-dependence of circadian locomotor output cycles kaput (CLOCK) down-regulation. Hepatocytes were challenged with oleic acid and WY-14643 to verify the action of PPARα in down-regulating CLOCK and lipid accumulation. Strongest NAFLD developed in mice fed 45%HFD and it was inhibited in WT mice. The night/day diet consumption ratio was inhibited more in WT mice than that in KO mice on 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 hPPARα in dosedependence of feno brate. According with the in vivo experiments, CLOCK down-regulation by activated PPARα was involved in inhibition of lipid accumulation 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.

PPARα is involved in high-fat diet-induced risk avoidance impairment via the regulation of hippocampal BDNF

“…On the other hand, the weight gain of the KO mice fed with a HFD was far less than that in the WT group, which was consistent with previous results. 25,26 Moreover, a HFD is typically associated with insulin resistance.…”

“…On the other hand, the weight gain of the KO mice fed with a HFD was far less than that in the WT group, which was consistent with previous results. 25,26 Moreover, a HFD is typically associated with insulin resistance. We conducted an OGTT and found that both the WT and KO mice fed with a HFD showed impaired glucose tolerance, indicating that PPARα null mice are not protected from the effects of the HFD.…”