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  • br Ethics approval br Availability of data

    2022-05-27


    Ethics approval
    Availability of data and materials
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    Competing interests
    Authors contributions
    Introduction Glucose supply to tissues is maintained through a complex regulatory network mostly driven by the pancreatic hormones insulin and glucagon which control glucose use, storage and synthesis. Through glycogenolysis and gluconeogenesis, the liver contributes to ∼70–80% of glucose production during an overnight fast, the remaining 30% coming from intestinal and kidney gluconeogenesis in physiological conditions.[2], [3] Glucagon-induced gluconeogenesis is the only source of glucose when glycogen stores are exhausted during fasting. Gluconeogenic substrates (lactate, alanine, and pyruvate) are funneled to mitochondria to generate oxaloacetate (OAA) through biotin-dependent pyruvate carboxylase. Cytosolic OAA is decarboxylated and phosphorylated to yield phosphoenolpyruvate (PEP), the primary building block of glucose, through phosphoenolpyruvate carboxylase (PEPCK), a rate-limiting enzyme of gluconeogenesis. Glycerol from triglyceride breakdown also contributes by varying extents to gluconeogenesis, feeding into the gluconeogenic pathway as glyceraldehyde-3-phosphate to generate fructose 1,6-biphosphate, the substrate of fructose 1,6-bisphosphatase (FBP1) which irreversibly yields fructose 6-phosphate (F6P). The regulation of hepatic glucose production (HGP) is achieved through a sophisticated signaling network involving post-translational protein modifications, allosteric regulation and transcription factor activation and repression[5], [6] which essentially control the gene Oxaprozin of three rate-limiting enzymes, glucose-6-phosphatase (G6pc), Fbp1 and PEPCK (Pck1) in a glucagon/cAMP-dependent manner.[8], [9], [10], [11] Multiple transcription factors orchestrate hepatic gluconeogenesis, such as PPARγ coactivator 1α (PGC1α), Forkhead box protein O1 (FOXO1), small heterodimer partner (SHP) and cAMP response element-binding protein (CREB), by regulating the expression of gluconeogenic genes. The nuclear bile acid (BA) receptor farnesoid X receptor (FXR) is a key regulator of essential hepatic functions. Besides acting on BA homeostasis and lipid metabolism, FXR participates in the regulation of glucose homeostasis. Sequestration of intestinal BAs decreases plasma glucose in patients with type 2 diabetes. This effect correlates with increased GLP-1 expression and secretion which may be attributed at least in part to FXR-mediated ChREBP inhibition in intestinal L-cells, a mechanism equally operative in the liver, where FXR represses glycolysis.[16], [17] Liver FXR controls HGP through the regulation of Pck1 and G6pc gene expression. Indeed, in vivo administration of natural or synthetic FXR agonists improves glucose tolerance, decreases Pck1 and G6pc expression and accordingly diminishes HGP in rodent models of obesity or diabetes.[18], [19], [20], [21], [22] Gene deletion studies mostly support a repressive role of FXR on gluconeogenesis,[18], [20] consistent with the reported inhibitory action of SHP, a direct FXR target gene, on gluconeogenic gene expression in vivo and in vitro.[23], [24] However, whereas FXR activation may improve glucose metabolism by downregulating HGP in pathological models of obesity and diabetes, its role in physiological fasting conditions appears different. Fxr−/− mice develop transient hypoglycemia and exhibit a delayed increase in HGP upon fasting.[25], [26], [27], [28] In addition, the induction of hepatic G6pc and Pck1 expression is significantly blunted in fasting Fxr−/− mice.[26], [29] Taken together, these data point to pro-gluconeogenic properties of FXR during fasting. Since the molecular mechanisms of FXR action in fasting are unknown, we studied the role of FXR in the control of HGP and gluconeogenic gene expression in physiological fasting.
    Materials and methods