Bile acids regulate hepatic gluconeogenic genes and farnesoid X receptor via Gαi-protein-coupled receptors and the AKT pathway

Abstract

Bile acids are important regulatory molecules that can activate specific nuclear receptors and cell signaling pathways in the liver and gastrointestinal tract. In the current study, the chronic bile fistula (CBF) rat model and primary rat hepatocytes (PRH) were used to study the regulation of gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) and the gene encoding short heterodimeric partner (SHP) by taurocholate (TCA). The intestinal infusion of TCA into the CBF rat rapidly (1 h) activated the AKT (∼9-fold) and ERK1/2 (3- to 5-fold) signaling pathways, downregulated (∼50%, 30 min) the mRNA levels of PEPCK and G-6-Pase, and induced (14-fold in 3 h) SHP mRNA. TCA rapidly (∼50%, 1–2 h) downregulated PEPCK and G-6-Pase mRNA levels in PRH. The downregulation of these genes by TCA was blocked by pretreatment of PRH with pertussis toxin (PTX). In PRH, TCA plus insulin showed a significantly stronger inhibition of glucose secretion/synthesis from lactate and pyruvate than either alone. The induction of SHP mRNA in PRH was strongly blocked by inhibition of PI3 kinase or PKCζ by specific chemical inhibitors or knockdown of PKCζ by siRNA encoded by a recombinant lentivirus. Activation of the insulin signaling pathway appears to be linked to the upregulation of farnesoid X receptor functional activity and SHP induction.

The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases

“…Activation of the AKT pathway by conjugated bile acids was shown to activate glycogen synthase activity in vitro and in vivo in a Gi-dependent manner (10). Further, conjugated bile acids were shown to repress the gluconeogenic genes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), both in vitro and in vivo (42). Importantly, repression of PEPCK and G6Pase mRNA by conjugated bile acids was shown to be pertussis toxin sensitive in primary rat hepatocytes.…”

“…Importantly, repression of PEPCK and G6Pase mRNA by conjugated bile acids was shown to be pertussis toxin sensitive in primary rat hepatocytes. Finally, it was reported that activation of the AKT pathway was required for optimal induction of small heterodimer partner (SHP) mRNA, an FXR target gene, by conjugated bile acids in vivo (42). It has also been reported that activation of the ERK1/2 pathway plays an important role in regulating the rate of turnover of SHP protein (43).…”

Nutritional Regulation of Bile Acid Metabolism Is Associated with Improved Pathological Characteristics of the Metabolic Syndrome

“…Nutritional Regulation of Endogenous BA Metabolism Modulates High Fat Diet-induced Hyperglycemia-Oral BA treatment reduces hyperglycemia in mice (12), possibly through reduced hepatic glucose output by repression of the Pck1 gene expression (13,14). In addition, PPAR␤/␦ activation reduces hepatic glucose output and improves peripheral glucose disposal (67).…”

“…Glucose metabolism is also regulated by bile acids, and mice treated with cholic acid are protected from diet-induced hyperglycemia (12) and have down-regulated liver expression of the gluconeogenic phosphoenolpyruvate carboxykinase (Pck1) gene (13,14). Furthermore, Fxr Ϫ/Ϫ mice are glucose-intolerant and insulin-resistant, and insulin signaling is blunted in several tissues (15)(16)(17).…”

Hypoglycemia occurs frequently in very low birth weight premature infants with cholestasis

“…15,16 Additionally, bile acids have been shown to rapidly activate G-protein coupled receptor(s), which activate the AKT insulin-signaling pathway. Japanese investigators demonstrated that bile acids, by stimulating the bile acid membrane receptor TGR5 (Takeda G-protein coupled receptor clone 5) release Glucagon like Peptide 1 (GLP1) from enterocytes lead to insulin secretion and glycogen synthesis.…”