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We found that ethanol feeding plus an acute binge decreased hepatic expression of TFEB, which is required for lysosomal biogenesis and autophagy. Strategies to block mTOR activity or increase levels of TFEB might be developed to protect the liver from ethanol-induced damage.

-Bile acids, steroids, and drugs activate steroid and xenobiotic receptor pregnane X receptor (PXR; NR1I2), which induces human cytochrome P4503A4 (CYP3A4) in drug metabolism and cholesterol 7␣-hydroxylase (CYP7A1) in bile acid synthesis in the liver. Rifampicin, a human PXR agonist, inhibits bile acid synthesis and has been used to treat cholestatic diseases. The objective of this study is to elucidate the mechanism by which PXR inhibits CYP7A1 gene transcription. The mRNA expression levels of CYP7A1 and several nuclear receptors known to regulate the CYP7A1 gene were assayed in human primary hepatocytes by quantitative real-time PCR (Q-PCR). Rifampicin reduced CYP7A1 and small heterodimer partner (SHP; NR02B) mRNA expression suggesting that SHP was not involved in PXR inhibition of CYP7A1. Rifampicin inhibited CYP7A1 reporter activity and a PXR binding site was localized to the bile acid response element-I. Mammalian two-hybrid assays revealed that PXR interacted with hepatic nuclear factor 4␣ (HNF4␣, NR2A1) and rifampicin was required. Coimmunoprecipitation assay confirmed PXR interaction with HNF4␣. PXR also interacted with peroxisome proliferator-activated receptor ␥ coactivator (PGC-1␣), which interacted with HNF4␣ and induced CYP7A1 gene transcription. Rifampicin enhanced PXR interaction with HNF4␣ and reduced PGC-1␣ interaction with HNF4␣. Chromatin immunoprecipitation assay showed that PXR, HNF4␣, and PGC-1␣ bound to CYP7A1 chromatin, and rifampicin dissociated PGC-1␣ from chromatin. These results suggest that activation of PXR by rifampicin promotes PXR interaction with HNF4␣ and blocks PGC-1␣ activation with HNF4␣ and results in inhibition of CYP7A1 gene transcription. Rifampicin inhibition of bile acid synthesis may be a protective mechanism against drug and bile acid-induced cholestasis.bile acid synthesis; gene regulation; nuclear receptors; peroxisome proliferator-activated receptor ␥ coactivator BILE ACID FEEDBACK INHIBITS bile acid synthesis by inhibiting the transcription of cholesterol 7␣-hydroxylase (CYP3A4), the rate-limiting enzyme in the bile acid biosynthetic pathway. This tightly regulated feedback mechanism is necessary because bile acids are highly toxic and cholesterol is needed for maintaining cellular structure and function. Recent studies (4) have revealed that bile acid feedback has far-reaching impacts on liver metabolism; it not only regulates bile acid synthesis in the digestive system but also regulates cholesterol, lipoprotein, triglyceride, and glucose metabolisms. The discovery that lithocholic acid (LCA) is an endogenous ligand for pregnane X receptor (PXR) suggests that bile acids may also regulate drug metabolism in the liver and intestine by induction of CYP450 enzymes (27, 34). PXR and its human ortholog steroid and xenobiotic receptor (SXR) induce the CYP3A, CYP2B, and CYP2C families of steroid-and drug-metabolizing enzymes in the liver and intestine (17). Despite the high-sequence identity in the ligand-binding domain between human and mouse PXR, they are very differ...

Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway that converts cholesterol into bile acids in the liver. Recent studies have shown that bile acids may play an important role in maintaining lipid, glucose, and energy homeostasis. However, the role of CYP7A1 in the development of obesity and diabetes is currently unclear. In this study, we demonstrated that transgenic mice overexpressing Cyp7a1 in the liver [i.e., Cyp7a1 transgenic (Cyp7a1-tg) mice] were resistant to high-fat diet (HFD)–induced obesity, fatty liver, and insulin resistance. Cyp7a1-tg mice showed increased hepatic cholesterol catabolism and an increased bile acid pool. Cyp7a1-tg mice had increased secretion of hepatic very low density lipoprotein but maintained plasma triglyceride homeostasis. Gene expression analysis showed that the hepatic messenger RNA expression levels of several critical lipogenic and gluconeogenic genes were significantly decreased in HFD-fed Cyp7a1-tg mice. HFD-fed Cyp7a1-tg mice had increased whole body energy expenditure and induction of fatty acid oxidation genes in the brown adipose tissue. Conclusion This study shows that Cyp7a1 plays a critical role in maintaining whole body lipid, glucose, and energy homeostasis. The induction of CYP7A1 expression with the expansion of the hydrophobic bile acid pool may be a potential therapeutic strategy for treating metabolic disorders such as fatty liver diseases, obesity, and diabetes in humans.

Summary Small molecule ligands that target to TGR5 and FXR have shown promise in treating various metabolic and inflammation-related human diseases. New insights into the mechanisms underlying the bariatric surgery and bile acid sequestrant treatment suggest that targeting the enterohepatic circulation to modulate gut-liver bile acid signaling, incretin production and microbiota represents a new strategy to treat obesity and type-2 diabetes.

Bile acids are synthesized from cholesterol in the liver. Some cytochrome P450 (CYP) enzymes play key roles in bile acid synthesis. Bile acids are physiological detergent molecules, so are highly cytotoxic. They undergo enterohepatic circulation and play important roles in generating bile flow and facilitating biliary secretion of endogenous metabolites and xenobiotics and intestinal absorption of dietary fats and lipid soluble vitamins. Bile acid synthesis, transport and pool size are therefore tightly regulated under physiological conditions. In cholestasis, impaired bile flow leads to accumulation of bile acids in the liver, causing hepatocyte and biliary injury and inflammation. Chronic cholestasis is associated with fibrosis, cirrhosis and eventually liver failure. Chronic cholestasis also increases the risk of developing hepatocellular or cholangiocellular carcinomas. Extensive research in the last two decades has shown that bile acids act as signaling molecules that regulate various cellular processes. The bile acid-activated nuclear receptors are ligand-activated transcriptional factors that play critical roles in the regulation of bile acid, drug and xenobiotic metabolism. In cholestasis, these bile acid-activated receptors regulate a network of genes involved in bile acid synthesis, conjugation, transport and metabolism to alleviate bile acid-induced inflammation and injury. Additionally, bile acids are known to regulate cell growth and proliferation, and altered bile acid levels in diseased conditions have been implicated in liver injury/regeneration and tumorigenesis. We will cover the mechanisms that regulate bile acid homeostasis and detoxification during cholestasis, and the roles of bile acids in the initiation and regulation of hepatic inflammation, regeneration and carcinogenesis.