Hepatocyte peroxisome proliferator-activated receptor α regulates bile acid synthesis and transport

Peroxisome proliferator-activated receptor alpha (PPAR alpha) controls lipid homeostasis through regulation of lipid transport and catabolism. PPAR alpha activators are clinically used for hyperlipidemia treatment. The role of PPAR alpha in bile acid (BA) homeostasis is beginning to emerge. Herein, Ppara-null and hepatocyte-specific Ppara-null (Ppara(Delta Hep)) as well as the respective wild-type mice were treated with the potent PPARa agonist Wy-14,643 (Wy) and global metabolomics performed to clarify the role of hepatocyte PPAR alpha in the regulation of BA homeostasis. Levels of all serum BAs were markedly elevated in Wy-treated wild-type mice but not in Ppara-null and Ppara(Delta Hep) mice. Gene expression analysis showed that PPAR alpha activation (1) down-regulated the expression of sodium-taurocholate acid transporting polypeptide and organic ion transporting polypeptide 1 and 4, responsible for the uptake of BAs into the liver; (2) decreased the expression of bile salt export pump transporting BA from hepatocytes into the bile canaliculus; (3) upregulated the expression of multidrug resistance-associated protein 3 and 4 transporting BA from hepatocytes into the portal vein. Moreover, there was a notable increase in the compositions of serum, hepatic and biliary cholic acid and taurocholic acid following Wy treatment, which correlated with the upregulated expression of the Cyp8b1 gene encoding sterol 12 alpha-hydroxylase. The effects of Wy were identical between the Ppara(Delta Hep) and Ppara-null mice. Hepatocyte PPAR alpha controlled BA synthesis and transport not only via direct transcriptional regulation but also via crosstalk with hepatic farnesoid X receptor signaling. These findings underscore a key role for hepatocyte PPAR alpha in the control of BA homeostasis.