The Transcription Factor 7-like 2 (TCF7L2) gene is associated with type 2 diabetes (T2D), but the function of the protein in metabolic tissues is controversial. The liver regulates whole body lipid and carbohydrate metabolism, and the development of T2D and nonalcoholic fatty liver disease (NAFLD) is linked to hepatic insulin resistance and dyslipidemia. The liver is metabolically zonated and hepatocytes are specialized to execute the diverse metabolic functions of the liver. We previously demonstrated that TCF7L2 transcriptionally regulates multiple metabolic pathways in hepatocytes, and hypothesized that TCF7L2 controls metabolic zonation in vivo. We generated mice expressing inactive TCF7L2 in liver (Hep-ΔE11-TCF7L2) and examined zonation, lipid metabolism and the development of NAFLD. We observed complete disruption of hepatic zonation in Hep-ΔE11-TCF7L2, as determined by the absence of glutamine synthetase expression in pericentral (PC) hepatocytes. Interestingly, using laser capture microdissection and TCF/LEF reporter mice, we observed that TCF7L2 and Wnt/β-catenin signaling genes were expressed throughout the liver, but that the activity of TCF7L2 was restricted to PC hepatocytes. Consistent with TCF7L2 activity in glycolytic PC hepatocytes only, Hep-ΔE11-TCF7L2 mice had normal glucose tolerance and insulin sensitivity. However, HFD-fed Hep-ΔE11-TCF7L2 mice were protected from adipose tissue expansion and weight gain, but had elevated circulating FFA. In a subset of Hep-ΔE11-TCF7 mice, we detected a severe NASH phenotype histologically, and RNA-Seq analysis revealed significant alterations in the expression of genes involved in cholesterol and lipid metabolism, and inflammatory and fibrotic pathways. These data show that TCF7L2 activity is highly restricted in mature liver, but that TCF7L2 is required for hepatic metabolic zonation. Our data also suggest that disrupted metabolic zonation may contribute to the development of NAFLD.


I.I. Ayala: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. L. Norton: None.


National Institutes of Health

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