Disturbances in the normal regulation of SREBP-sensitive genes in PPARα-deficient mice

Peroxisome proliferator-activated receptor α (PPARα)-null mice were used to investigate the nature of the relationship between the normal circadian rhythm of hepatic PPARα expression and the expression of the lipogenic and cholesterogenic sterol regulatory element-binding protein (SREBP)-regulated genes, acetyl-CoA carboxylase, fatty acid synthase (FAS), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR). The expression of FAS and HMG-CoAR varied rhythmically over the diurnal cycle in the normal mice, with patterns that were the opposite of that of PPARα. The diurnal variation of lipogenic and cholesterogenic gene expression was attenuated or abolished in the PPARα-null mice. This resulted in decreased expression compared with normal mice, but only during the dark phase of the cycle, when food intake was high. The diurnal variation in hepatic fatty acid and cholesterol synthesis was also abolished in the PPARα-null animals and the variations in the concentration of plasma triacylglycerol, nonesterified fatty acids, and cholesterol were all attenuated. The failure of HMG-CoAR expression to increase during the feeding period in the PPARα-null mice was associated with a decrease in hepatic nonesterified cholesterol content and an increase in cholesteryl ester compared with normal mice. There was no defect in the downregulation of hepatic HMG-CoAR mRNA in response to dietary cholesterol in the PPARα-null mice. Under these conditions, hepatic PPARγ expression increased in both the control and PPARα-deficient mice. The results suggest that PPARα-deficiency disturbs the normal circadian regulation of certain SREBP-sensitive genes in the liver, but does not affect their response to dietary cholesterol. —Patel, D. D., B. L. Knight, D. Wiggins, S. M. Humphreys, and G. F. Gibbons. Disturbances in the normal regulation of SREBP-sensitive genes in PPARα-deficient mice.