FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Cell metabolism (Impact Factor: 17.57). 06/2011; 13(6):729-38. DOI: 10.1016/j.cmet.2011.03.019
Source: PubMed


Regulation of hepatic carbohydrate homeostasis is crucial for maintaining energy balance in the face of fluctuating nutrient availability. Here, we show that the hormone fibroblast growth factor 15/19 (FGF15/19), which is released postprandially from the small intestine, inhibits hepatic gluconeogenesis, like insulin. However, unlike insulin, which peaks in serum 15 min after feeding, FGF15/19 expression peaks approximately 45 min later, when bile acid concentrations increase in the small intestine. FGF15/19 blocks the expression of genes involved in gluconeogenesis through a mechanism involving the dephosphorylation and inactivation of the transcription factor cAMP regulatory element-binding protein (CREB). This in turn blunts expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and other genes involved in hepatic metabolism. Overexpression of PGC-1α blocks the inhibitory effect of FGF15/19 on gluconeogenic gene expression. These results demonstrate that FGF15/19 works subsequent to insulin as a postprandial regulator of hepatic carbohydrate homeostasis.

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Available from: Robert D Gerard, Oct 01, 2015
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    • "(M+3). WT and Mpc1 LivKO mice were administered U 13 Clactate and -pyruvate by intraperitoneal injection as performed previously (Potthoff et al., 2011). To capture flux data under near-equilibrium gluconeogenic conditions, livers were harvested and immediately freeze-clamped at 30 min post-injection , the expected time of plateau for blood glucose and lactate concentrations. "
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    ABSTRACT: Gluconeogenesis is critical for maintenance of euglycemia during fasting. Elevated gluconeogenesis during type 2 diabetes (T2D) contributes to chronic hyperglycemia. Pyruvate is a major gluconeogenic substrate and requires import into the mitochondrial matrix for channeling into gluconeogenesis. Here, we demonstrate that the mitochondrial pyruvate carrier (MPC) comprising the Mpc1 and Mpc2 proteins is required for efficient regulation of hepatic gluconeogenesis. Liver-specific deletion of Mpc1 abolished hepatic MPC activity and markedly decreased pyruvate-driven gluconeogenesis and TCA cycle flux. Loss of MPC activity induced adaptive utilization of glutamine and increased urea cycle activity. Diet-induced obesity increased hepatic MPC expression and activity. Constitutive Mpc1 deletion attenuated the development of hyperglycemia induced by a high-fat diet. Acute, virally mediated Mpc1 deletion after diet-induced obesity decreased hyperglycemia and improved glucose tolerance. We conclude that the MPC is required for efficient regulation of gluconeogenesis and that the MPC contributes to the elevated gluconeogenesis and hyperglycemia in T2D.
    Cell metabolism 09/2015; DOI:10.1016/j.cmet.2015.07.027 · 17.57 Impact Factor
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    • "By contrast, Ma et al. observed that FXR activation by CA suppressed the expression of multiple genes in the gluconeogenic pathway, including PEPCK, PGC-1α, and G-6-Pase [58]. Recent studies have also shown that mouse FGF15 and human FGF19, postprandial hormone induced by FXR, inhibit hepatic gluconeogenesis through a mechanism involving the dephosphorylation and inactivation of the transcription factor cAMP regulatory element binding protein (CREB) [59]. Nevertheless, a recent observation may provide a more reasonable illustration for the discrepancies that FXR activation exerts opposite effects during the transition from the unfed state to the fed state. "
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    ABSTRACT: Type 2 diabetes (T2D) is the most prevalent metabolic disease, and many people are suffering from its complications driven by hyperglycaemia and dyslipidaemia. Nuclear receptors (NRs) are ligand-inducible transcription factors that mediate changes to metabolic pathways within the body. As metabolic regulators, the farnesoid X receptor (FXR) and the liver X receptor (LXR) play key roles in the pathogenesis of T2D, which remains to be clarified in detail. Here we review the recent progress concerning the physiological and pathophysiological roles of FXRs and LXRs in the regulation of bile acid, lipid and glucose metabolism and the implications in T2D, taking into account that these two nuclear receptors are potential pharmaceutical targets for the treatment of T2D and its complications.
    International Journal of Endocrinology 04/2014; 2014(5):751859. DOI:10.1155/2014/751859 · 1.95 Impact Factor
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    • "Cell Metabolism 17, 916–928, June 4, 2013 ª2013 Elsevier Inc. 921 FGF15-expressing adenovirus dramatically reduced Cyp7a1 expression in B6By mouse liver (Figure 4C). In addition to bile acid synthesis, FGF15 inhibits hepatic glucose production (Potthoff et al., 2011). Consistent with this, administration of FGF15 also reduced the fasting glucose levels observed in B6By mice, and this was reflected in reduced expression of glucose-6 phosphatase (Figure 4C). "
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    ABSTRACT: Hepatic bile acid synthesis is controlled, in part, by a complex enterohepatic feedback regulatory mechanism. In this review, we focus on the role of the intestinal FGF15/19 hormone in modulating bile acid levels, and additional metabolic effects on glucose metabolism, nonalcoholic liver disease (NAFLD), and liver regeneration. We also highlight the newly identified intestinal protein, Diet1, which is a modulator of FGF15/19 levels. Low FGF19 levels are associated with bile acid diarrhea and NAFLD. In contrast, high FGF19 levels are associated with diabetes remission following Roux-en-Y gastric bypass surgery, suggesting new therapeutic approaches against type 2 diabetes. The effect of FGF15/19 on liver plasticity is a double-edged sword: whereas elevated FGF15/19 levels improve survival of mice after partial hepatectomy, FGF19 mitogenic activity is associated with liver carcinoma. Finally, a recent study has identified Diet1, an intestinal factor that influences FGF15/19 levels in mouse intestine and human enterocytes. Diet1 represents the first factor shown to influence FGF15/19 levels at a post-transcriptional level. The biological effects of FGF15/19 make it an attractive target for treating metabolic dysregulation underlying conditions such as fatty liver and type 2 diabetes. Further elucidation of the role of Diet1 in FGF15/19 secretion may provide a control point for the pharmacological modulation of FGF15/19 levels.
    Current opinion in lipidology 02/2014; 25(2). DOI:10.1097/MOL.0000000000000060 · 5.66 Impact Factor
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