Hif-1α expression targets the TMA/Fmo3/TMAO axis to participate in gallbladder cholesterol stone formation in individuals living in plateau regions.

The incidence of gallbladder cholesterol stones (GCS) increases rapidly among people living in high-altitude hypoxic environments compared to those in normoxic areas. Upregulation of hepatic hypoxia inducible factor 1α (Hif-1α) plays a key role in the formation of GCS. High plasma trimethylamine-N-oxide (TMAO) levels are positively correlated with the occurrence of GCS. We hypothesized that HIF-1α may upregulate TMAO levels by promoting the transcription of flavin-containing monooxygenase 3 (Fmo3), which eventually leads to GCS formation. Our study shows that in women, high plasma total cholesterol and apolipoprotein B were positively correlated with cholecystolithiasis and hypoxia. Hif-1α binds to the Fmo3 promoter and promotes Fmo3 expression. Hypoxia and lithogenic diet induce the expression of Hif-1α, Fmo3, TMAO and cholesterol tube transporters in the livers of mice, disturb the proportion of bile and plasma components, and induce the formation of GCS. In cell experiments, silencing Hif-1α downregulates the expression of Fmo3, TMAO and cholesterol tube transporters. In a mouse model of hypoxic cholecystolithiasis, silencing Hif-1α downregulates the expression of related genes, restores the proportion of bile and plasma lipid components, and reduces the formation of GCS. Our study shows that Hif-1α binds to the promoter region of Fmo3 and promotes Fmo3 transcription. Thus, it mediates the transcriptional activation of the TMA/Fmo3/TMAO pathway, upregulates the expression of ATP-binding cassettes (Abc) g5 and g8, and participates in the regulation of the occurrence of GCS in the plateau region.

The role of hypoxia-inducible factor 1α in hepatic lipid metabolism.

Chronic liver disease is a major public health problem with a high and increasing prevalence worldwide. In the progression of chronic liver disease, steatosis drives the progression of the disease to cirrhosis or even liver cancer. Hypoxia-inducible factor 1α (HIF-1α) is central to the regulation of hepatic lipid metabolism. HIF-1α upregulates the expression of genes related to lipid uptake and synthesis in the liver and downregulates the expression of lipid oxidation genes. Thus, it promotes intrahepatic lipid deposition. In addition, HIF-1α is expressed in white adipose tissue, where lipolysis releases free fatty acids (FFAs) into the blood. These circulating FFAs are taken up by the liver and accumulate in the liver. The expression of HIF-1α in the liver condenses bile and makes it easier to form gallstones. Contrary to the role of hepatic HIF-1α, intestinal HIF-1α expression can maintain a healthy microbiota and intestinal barrier. Thus, it plays a protective role against hepatic steatosis. This article aims to provide an overview of the current understanding of the role of HIF-1α in hepatic steatosis and to encourage the development of therapeutic agents associated with HIF-1α pathways. KEY MESSAGES: • Hepatic HIF-1α expression promotes lipid uptake and synthesis and reduces lipid oxidation leading to hepatic steatosis. • The expression of HIF-1α in the liver condenses bile and makes it easier to form gallstones. • Intestinal HIF-1α expression can maintain a healthy microbiota and intestinal barrier.

Gab1 regulates invadopodia and autocrine VEGF through SHP2/ERK1/2 in hilar cholangiocarcinoma cells.

OBJECTIVES: Hilar cholangiocarcinoma is the most common malignant tumors of the biliary tract and it has high invasiveness. Invadopodia and autocrine vascular endothelial growth factor (VEGF) are closely related to tumor invasiveness. We investigated the role of Grb2-associated binder 1 (Gab1) in invadopodia and autocrine VEGF in hilar cholangiocarcinoma cells. METHODS: The expression of Gab1 and vascular endothelial growth factor receptor 2 (VEGFR-2) in tumor cells was detected by real-time PCR. MTT, flow cytometry and transwell assays were used to determine the effect of Gab1 on the biological behavior of tumor cells. In situ gelatin zymogram, western blotting, ELISA and immunofluorescence were used to study Gab1- and apatinib-regulated invadopodia, epithelial-mesenchymal transition (EMT), and VEGF autocrine signaling through the SHP2/ERK1/2 pathway. RESULTS: Gab1 controlled invadopodia maturation via the regulation of cortactin and EMT. Additionally, Gab1-regulated autocrine VEGF was observed in tumor cells expressing VEGFR-2, and endogenous and exogenous VEGF regulated VEGF expression through p-VEGFR-2 nuclear aggregation. Furthermore, the Gab1/SHP2/ERK1/2 axis regulated invadopodia and VEGF autocrine function in tumor cells. Finally, apatinib inhibited the malignant behavior of tumor cells and the nuclear aggregation of p-VEGFR-2 by inhibiting the phosphorylation of VEGFR-2 (direct) and the expression of Gab1 (indirect) in tumor cells. CONCLUSIONS: This study demonstrates that Gab1 and apatinib affect tumor cell invadopodia and autocrine VEGF expression through the Gab1/SHP2/ERK1/2 axis in hilar cholangiocarcinoma cells.

Kaempferol alleviates acute alcoholic liver injury in mice by regulating intestinal tight junction proteins and butyrate receptors and transporters.

An impaired gut-liver axis is a potential factor that contributes to alcoholic liver disease. Specifically, ethanol decreases intestinal integrity and causes gut dysbiosis. Butyrate, a fermentation byproduct of gut microbiota, is negatively altered following acute ethanol exposure. This study aimed to determine whether kaempferol could protect against alcoholic liver injury (AALI) in mice by regulating tight junction (TJ) proteins and butyrate receptors and transporters in intestines. Male Institute of Cancer Research (ICR) mice were randomly divided into five treatment groups: control, ethanol administered (5 g/kg), and the low-, medium- and high-dosage kaempferol (25, 50, 100 mg/kg) treatments. Intestinal expression was evaluated for the TJ proteins ZO-1 and occludin and the butyrate receptor GPR109A and butyrate transporter SLC58A proteins, in addition to plasma ALT and AST levels and pathomorphological changes in liver and intestinal tissues. The expression of the TJ proteins ZO-1 and occludin, butyrate receptors, and butyrate transporters in the ileum and proximal colon decreased in AALI mice, while plasma ALT and AST levels markedly increased. Kaempferol supplementation reversed these effects. These results suggest that kaempferol could serve as a prophylactic treatment against AALI in mice by increasing the expression of butyrate receptors, transporters, and TJ proteins in the intestinal mucosa.