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Bile acid (BA) biosynthesis is tightly controlled by intrahepatic negative feedback signaling elicited by BA binding to farnesoid X receptor (FXR) and also by enterohepatic communication involving ileal BA reabsorption and FGF15/19 secretion. However, how these pathways are coordinated is poorly understood. We show here that nonreceptor tyrosine phosphatase Shp2 is a critical player that couples and regulates the intrahepatic and enterohepatic signals for repression of BA synthesis. Ablating Shp2 in hepatocytes suppressed signal relay from FGFR4, receptor for FGF15/19, and attenuated BA activation of FXR signaling, resulting in elevation of systemic BA levels and chronic hepatobiliary disorders in mice. Acting immediately downstream of FGFR4, Shp2 associates with FRS2α and promotes the receptor activation and signal relay to several pathways. These results elucidate a molecular mechanism for the control of BA homeostasis by Shp2 through the orchestration of multiple signals in hepatocytes.

Objective: To explore mechanism of hedyotis diffusa extract attenuating acute pancreatitis (AP) lung injury in rats from 5'-adenosine monophosphate activated protein kinase (AMPK)/autophagy-related protein 5 (ATG5) signaling pathway. Methods: AP lung injury rat model was established, and rats were randomly divided into model group, extract (hedyotis diffusa extract) group, 3-MA (autophagy inhibitor 3-methyladenine) group, AICAR (AMPK activator) group and extract+AICAR group, with 15 rats in each group, and another 15 rats were selected as sham operation group. ELISA was performed to determine levels of serum amylase (AMY), IL-1β, IL-6 and IL-18; amount of ascites and proportion of lung wet/dry (W/D) in rats were determined; HE was performed to observe pathological damage of pancreas and lung tissues; Western blot was performed to determine lysosomal-associated membrane protein 2 (LAMP2), autophagy substrate p62, IL-1β precursor protein (pro-IL-1β), trypsinogen activation peptide (TAP), AMPK, p-AMPK, ATG5, autophagy marker LC3-II/I, ubiquitin-specific protease 10 (UPS10) expressions. Results: Compared with sham operation group, ascites volume, lung W/D, pancreas and lung tissue pathological damage scores, serum AMY, IL-1β, IL-6, IL-18 levels, pancreatic tissue p62, TAP, pro-IL-1β expressions, lung tissue p-AMPK/AMPK, ATG5, LC3-II/I, UPS10, pro-IL-1β expressions of rats in model group were increased (P<0.05), while LAMP2 protein expression in pancreas and lung tissue was decreased (P<0.05); after model rats were intervened by hedyotis diffusa extract or autophagy inhibitor 3-MA, the above indexes were significantly improved (P<0.05), and improvement effect of hedyotis diffusa extract was better than 3-MA (P<0.05); while AMPK activator AICAR could attenuate improvement effect of hedyotis diffusa extract on lung injury in AP rats (P<0.05). Conclusion: Hedyotis diffusa extract can reduce inflammatory response and autophagy level by inhibiting AMPK/ATG5 signaling pathway, and improve lung injury in AP rats. [ABSTRACT FROM AUTHOR]

The rapid growth of on-demand ride service platforms has made it increasingly important for these platforms to efficiently match services by understanding driver characteristics and consumer preferences. This paper aims to investigate the pricing strategy by considering the impact of consumer preference heterogeneity and the different service types offered by drivers. The findings of this study reveal the need for the platform to strike a balance between service cost and the benefits of high-quality drivers, which can be referred to as the "cost-performance ratio". If the "cost-performance ratio" that attracts high-quality drivers is high, the platform will attract high-quality drivers or drivers of all types to participate while offering differentiated services. Otherwise, the platform will only provide services through low-quality drivers. Furthermore, the platform will also consider when to offer differentiated services based on network externalities and service quality. When the network externalities of the two types of services are similar, the platform will differentiate them based on service quality differences. Overall, considering consumer preference heterogeneity, drivers of service types, and network externalities, this paper provides guidance for platforms to make optimal decisions that enhance their service offerings and improve overall customer satisfaction. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. Clarifying the molecular mechanism of lipid metabolism is crucial for the treatment of NAFLD. We examined miR-192-5p levels in the livers of mice in which NAFLD was induced via a high-fat diet (HFD), as well as in mouse primary hepatocytes and human HepG2 cells treated with free fatty acids (FFAs). MiR-192-5p inhibitor was administered to NAFLD mice and hepatocytes to verify the specific function of miR-192-5p in NAFLD. We validated the target gene of miR-192-5p and further illustrated the effects of this miRNA on the regulation of triglyceride (TG) metabolism. We found that miR-192-5p was significantly increased in the livers of NAFLD mice and FFA-treated hepatocytes. Inhibition of miR-192-5p increased the accumulation of hepatic TGs and aggravated hepatic steatosis in NAFLD mice. In FFA-treated hepatocytes, miR-192-5p inhibitors markedly increased TG content, whereas overexpression of miR-192-5p reduced TG levels. Yin Yang 1 (Yy1) was identified as the target gene of miR-192-5p, which regulates TG synthesis via the YY1/fatty-acid synthase (FASN) pathway. Our results demonstrated that miR-192-5p should be considered a protective regulator in NAFLD that can inhibit hepatic TG synthesis by targeting Yy1. [ABSTRACT FROM AUTHOR]