Bochkis IM, Rubins NE, White P, Furth EE, et al Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress. Nat Med. 2008;14(8):828-836

Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
Nature medicine (Impact Factor: 27.36). 08/2008; 14(8):828-36. DOI: 10.1038/nm.1853
Source: PubMed


Production of bile by the liver is crucial for the absorption of lipophilic nutrients. Dysregulation of bile acid homeostasis can lead to cholestatic liver disease and endoplasmic reticulum (ER) stress. We show by global location analysis ('ChIP-on-chip') and cell type-specific gene ablation that the winged helix transcription factor Foxa2 is required for normal bile acid homeostasis. As suggested by the location analysis, deletion of Foxa2 in hepatocytes in mice using the Cre-lox system leads to decreased transcription of genes encoding bile acid transporters on both the basolateral and canalicular membranes, resulting in intrahepatic cholestasis. Foxa2-deficient mice are strikingly sensitive to a diet containing cholic acid, which results in toxic accumulation of hepatic bile salts, ER stress and liver injury. In addition, we show that expression of FOXA2 is markedly decreased in liver samples from individuals with different cholestatic syndromes, suggesting that reduced FOXA2 abundance could exacerbate the injury.

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    • "Nuclear extracts preparation and protein immunoblot analysis were performed as reported previously (Bochkis et al., 2008). The primary antibodies used were rabbit antibody to FOXA2 (Seven Hills Bioreagents, WRAB-1200, 1:5,000), rabbit antibody to HDAC3 (Abcam, ab7030, 1:5,000), rabbit antibody to PPARa (Santa Cruz, sc-9000, 1:100), rabbit antibody to PPARg (Santa Cruz, sc-7196, 1:100), rabbit antibody to SRF (Santa Cruz, sc-335, 1:200), and rabbit antibody to TBP (Santa Cruz, sc-273, 1:100). "
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    • "Low pancreatic FoxA2 expression level is proven to be positively correlated with insulin resistance and the risk of T2DM27. Interestingly, the liver of FoxA2-deficient mice had shown high bile acid accumulation28. In addition, it has been proposed that a high intracellular Cl– in the β-cell of pancreas is essential to electrical activity of β-cell membrane and insulin release29.Considering all these, we presumed that probiotic pretreatment protects the pancreas in high-fat-sucrose fed rats by enhancing pancreatic ClC-2 expression and eliminating bile acids in feces through a bile acid–chloride exchanging mechanism. "
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    • "The mammalian Forkhead transcription factor FOXA2 is a key regulator of hepatic energy metabolism in mammals [1]. Besides its role in regulating liver and other endoderm-derived organ specification during embryonic development [2], in post-natal life Foxa2 controls essential metabolic processes including glucose metabolism [3], [4], bile acid homeostasis [5] and lipid oxidation [6], [7]. Hepatocyte-specific Foxa2 conditional knockout mice showed impaired glucose homeostasis during the fasting response [3] and Foxa2 heterozygous mice displayed increased adiposity and impaired glucose uptake when challenged with a high fat diet [6], [8]. "
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