The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.

Objectives: To determine the prevalence of nonalcoholic fatty liver disease (NAFLD) in children with obesity because current estimates range from 1.7% to 85%. A second objective was to evaluate the diagnostic accuracy of alanine aminotransferase (ALT) for NAFLD in children with obesity. Study Design:We evaluated children ages 9-17 years with obesity for the presence of NAFLD. Diseases other than NAFLD were excluded by history and laboratories. Hepatic steatosis was measured by liver magnetic resonance imaging (MRI) proton density fat fraction (PDFF). The diagnostic accuracy of ALT for detecting NAFLD was evaluated. Results:The study included 408 children with obesity that had a mean age of 13.2 years and mean BMI percentile of 98.0. The study population had a mean ALT of 32 U/L and median hepatic MRI-PDFF of 3.7%. The estimated prevalence of NAFLD was 26.0% (95% CI 24.2 -27.7), 29.4% in males (CI 26.1 -32.7%) and 22.6% in females (CI 16.0 -29.1%). Optimal ALT cut-point was 42 U/L (47.8% sensitivity, 93.2% specificity) for males and 30 U/L (52.1% sensitivity, 88.8% specificity) for females. CART model with sex, ALT, and insulin had 80% diagnostic accuracy for NAFLD.

Peroxisome proliferator-activated receptor delta (PPARδ), a member of the nuclear receptor family, is emerging as a key metabolic regulator with pleiotropic actions on various tissues including fat, skeletal muscle, and liver. Here we show that the PPARδ agonist KD3010, but not the well-validated GW501516, dramatically ameliorates liver injury induced by carbon tetrachloride (CCl 4 ) injections. Deposition of extracellular matrix proteins was lower in the KD3010-treated group than in the vehicle-or GW501516-treated group. Interestingly, profibrogenic connective tissue growth factor was induced significantly by GW501516, but not by KD3010, following CCl 4 treatment. The hepatoprotective and antifibrotic effect of KD3010 was confirmed in a model of cholestasis-induced liver injury and fibrosis using bile duct ligation for 3 wk. Primary hepatocytes treated with KD3010 but not GW501516 were protected from starvation or CCl 4 -induced cell death, in part because of reduced reactive oxygen species production. In conclusion, our data demonstrate that an orally active PPARδ agonist has hepatoprotective and antifibrotic effects in animal models of liver fibrosis, suggesting a possible mechanistic and therapeutic approach in treating patients with chronic liver diseases.

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/17-3-reading-yu a video presentation of this article http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/17-3-interview-yu an interview with the author