| First Author | Pan X | Year | 2020 |
| Journal | J Clin Invest | Volume | 130 |
| Issue | 8 | Pages | 4282-4300 |
| PubMed ID | 32396530 | Mgi Jnum | J:301629 |
| Mgi Id | MGI:6506883 | Doi | 10.1172/JCI132765 |
| Citation | Pan X, et al. (2020) Nonalcoholic fatty liver disease in CLOCK mutant mice. J Clin Invest 130(8):4282-4300 |
| abstractText | Nonalcoholic fatty liver disease (NAFLD) is becoming a major health issue as obesity increases around the world. We studied the effect of a circadian locomotor output cycles kaput (CLOCK) mutant (ClkDelta19/Delta19) protein on hepatic lipid metabolism in C57BL/6 Clkwt/wt and apolipoprotein E-deficient (Apoe-/-) mice. Both ClkDelta19/Delta19 and ClkDelta19/Delta19 Apoe-/- mice developed a full spectrum of liver diseases (steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma) recognized in human NAFLD when challenged with a Western diet, lipopolysaccharide, or CoCl2. We identified induction of CD36 and hypoxia-inducible factor 1alpha (HIF1alpha) proteins as contributing factors for NAFLD. Mechanistic studies showed that WT CLOCK protein interacted with the E-box enhancer elements in the promoters of the proline hydroxylase domain (PHD) proteins to increase expression. In ClkDelta19/Delta19 mice, PHD levels were low, and HIF1alpha protein levels were increased. When its levels were high, HIF1alpha interacted with the Cd36 promoter to augment expression and enhance fatty acid uptake. Thus, these studies establish a regulatory link among circadian rhythms, hypoxia response, fatty acid uptake, and NAFLD. The mouse models described here may be useful for further mechanistic studies in the progression of liver diseases and in the discovery of drugs for the treatment of these disorders. |
