Peroxisome-proliferator-activated receptor-α (PPARα) deficiency leads to dysregulation of hepatic lipid and carbohydrate metabolism by fatty acids and insulin

Abstract

The aim of the present study was to determine whether peroxisome-proliferator-activated receptor-α (PPARα) deficiency disrupts the normal regulation of triacylglycerol (TAG) accumulation, hepatic lipogenesis and glycogenesis by fatty acids and insulin using PPARα-null mice. In wild-type mice, hepatic TAG concentrations increased (P<0.01) with fasting (24h), with substantial reversal after refeeding (6h). Hepatic TAG levels in fed PPARα-null mice were 2.4-fold higher than in the wild-type (P<0.05), increased with fasting, but remained elevated after refeeding. PPARα deficiency also impaired hepatic glycogen repletion (P<0.001), despite normal insulin and glucose levels after refeeding. Higher levels of plasma insulin were required to support similar levels of hepatic lipogenesis de novo (3H2O incorporation) in the PPARα-null mice compared with the wild-type. This difference was reflected by corresponding changes in the relationship between plasma insulin and the mRNA expression of the lipogenic transcription factor sterol-regulatory-element-binding protein-1c, and that of one of its known targets, fatty acid synthase. In wild-type mice, hepatic pyruvate dehydrogenase kinase (PDK) 4 protein expression (a downstream marker of altered fatty acid catabolism) increased (P<0.01) in response to fasting, with suppression (P<0.001) by refeeding. Although PDK4 up-regulation after fasting was halved by PPARα deficiency, PDK4 suppression after refeeding was attenuated. In summary, PPARα deficiency leads to accumulation of hepatic TAG and elicits dysregulation of hepatic lipid and carbohydrate metabolism, emphasizing the importance of precise control of lipid oxidation for hepatic fuel homoeostasis.