Bile acid homeostasis in female mice deficient in

Bile acids (BAs) are amphipathic molecules important for metabolism of cholesterol, absorption of lipids and lipid soluble vitamins, bile flow, and regulation of gut microbiome. There are over 30 different BA species known to exist in humans and mice, which are endogenous modulators of at least 6 different membrane or nuclear receptors. This diversity of ligands and receptors play important roles in health and disease; however, the full functions of each individual BA

Effects of total parenteral nutrition on drug metabolism gene expression in mice

Parenteral nutrition-associated liver disease (PNALD) is a liver dysfunction caused by various risk factors presented in patients receiving total parenteral nutrition (TPN). Omega-6 rich Intralipid® and omega-3 rich Omegaven® are two intravenous lipid emulsions used in TPN. TPN could affect the hepatic expression of genes in anti-oxidative stress, but it's unknown whether TPN affects genes in drug metabolism. In this study, either Intralipid®- or Omegaven®-based TPN was administered to mice and the expression of a cohort of genes involved in anti-oxidative stress or drug metabolism was analyzed, glutathione (GSH) levels were measured, and protein levels for two key drug metabolism genes were determined. Overall, the expression of most genes was downregulated by Intralipid®-based TPN ( and ). Omegaven® showed similar results as Intralipid® except for preserving the expression of and and increasing . Total GSH levels were decreased by Intralipid®, but increased by Omegaven®. CYP3A11 protein levels were increased by Omegaven®. In conclusion, TPN reduced the expression of many genes involved in anti-oxidative stress and drug metabolism in mice. However, Omegaven® preserved expression of , suggesting another beneficial effect of Omegaven® in protecting liver functions.

Role of farnesoid X receptor in establishment of ontogeny of phase-I drug metabolizing enzyme genes in mouse liver

The expression of phase-I drug metabolizing enzymes in liver changes dramatically during postnatal liver maturation. Farnesoid X receptor (FXR) is critical for bile acid and lipid homeostasis in liver. However, the role of FXR in regulating ontogeny of phase-I drug metabolizing genes is not clear. Hence, we applied RNA-sequencing to quantify the developmental expression of phase-I genes in both-null and control (C57BL/6) mouse livers during development. Liver samples of male C57BL/6 and-null mice at 6 different ages from prenatal to adult were used. The-null showed an overall effect to diminish the "day-1 surge" of phase-I gene expression, including cytochrome P450s at neonatal ages. Among the 185 phase-I genes from 12 different families, 136 were expressed, and differential expression during development occurred in genes from all 12 phase-I families, including hydrolysis: carboxylesterase (), paraoxonase (), and epoxide hydrolase (); reduction: aldoketo reductase (), quinone oxidoreductase (), and dihydropyrimidine dehydrogenase (); and oxidation: alcohol dehydrogenase (), aldehyde dehydrogenase (), flavin monooxygenases (), molybdenum hydroxylase (and), cytochrome P450 (P450), and cytochrome P450 oxidoreductase (). The data also suggested new phase-I genes potentially targeted by FXR. These results revealed an important role of FXR in regulation of ontogeny of phase-I genes.

Fatty liver diseases, bile acids, and FXR

The prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide has increased at an alarming rate, which will likely result in enormous medical and economic burden. NAFLD presents as a spectrum of liver diseases ranging from simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even to hepatocellular carcinoma (HCC). A comprehensive understanding of the mechanism(s) of NAFLD-to-NASH transition remains elusive with various genetic and environmental susceptibility factors possibly involved. An understanding of the mechanism may provide novel strategies in the prevention and treatment to NASH. Abnormal regulation of bile acid homeostasis emerges as an important mechanism to liver injury. The bile acid homeostasis is critically regulated by the farnesoid X receptor (FXR) that is activated by bile acids. FXR has been known to exert tissue-specific effects in regulating bile acid synthesis and transport. Current investigations demonstrate FXR also plays a principle role in regulating lipid metabolism and suppressing inflammation in the liver. Therefore, the future determination of the molecular mechanism by which FXR protects the liver from developing NAFLD may shed light to the prevention and treatment of NAFLD.

Farnesoid X receptor, the bile acid sensing nuclear receptor, in liver regeneration

The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively studied in the past using the partial hepatectomy (PH) model in rodents, where 2/3 PH is carried out by removing two lobes. The whole process of liver regeneration is complicated, orchestrated event involving a network of connected interactions, which still remain fully elusive. Bile acids (BAs) are ligands of farnesoid X receptor (FXR), a nuclear receptor of ligand-activated transcription factor. FXR has been shown to be highly involved in liver regeneration. BAs and FXR not only interact with each other but also regulate various downstream targets independently during liver regeneration. Moreover, recent findings suggest that tissue-specific FXR also contributes to liver regeneration significantly. These novel findings suggest that FXR has much broader role than regulating BA, cholesterol, lipid and glucose metabolism. Therefore, these researches highlight FXR as an important pharmaceutical target for potential use of FXR ligands to regulate liver regeneration in clinic. This review focuses on the roles of BAs and FXR in liver regeneration and the current underlying molecular mechanisms which contribute to liver regeneration.