FGFR4 prevents hyperlipidemia and insulin resistance but underlies high-fat diet-induced fatty liver

Xinqiang Huang, Chaofeng Yang, Yongde Luo, Chengliu Jin, Fen Wang, Wallace L. McKeehan

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

OBJECTIVE - Fibroblast growth factor (FGF) family signaling largely controls cellular homeostasis through short-range inter-cell paracrine communication. Recently FGF15/19, 21, and 23 have been implicated in endocrine control of metabolic homeostasis. The identity and location of the FGF receptor isotypes that mediate these effects are unclear. The objective was to determine the role of FGFR4, an isotype that has been proposed to mediate an ileal FGF15/19 to hepatocyte FGFR4 axis in cholesterol homeostasis, in metabolic homeostasis in vivo. RESEARCH DESIGN AND METHODS - FGFR4-/- mice - mice overexpressing constitutively active hepatic FGFR4 - and FGFR4 -/- with constitutively active hepatic FGFR4 restored in the liver were subjected to a normal and a chronic high-fat diet sufficient to result in obesity. Systemic and liver-specific metabolic phenotypes were then characterized. RESULTS - FGFR4-deficient mice on a normal diet exhibited features of metabolic syndrome that include increased mass of white adipose tissue, hyperlipidemia, glucose intolerance, and insulin resistance, in addition to hypercholesterolemia. Surprisingly, the FGFR4 deficiency alleviated high-fat diet-induced fatty liver in obese mice, which is also a correlate of metabolic syndrome. Restoration of FGFR4, specifically in hepatocytes of FGFR4-deficient mice, decreased plasma lipid levels and restored the high-fat diet-induced fatty liver but failed to restore glucose tolerance and sensitivity to insulin. CONCLUSIONS - FGFR4 plays essential roles in systemic lipid and glucose homeostasis. FGFR4 activity in hepatocytes that normally serves to prevent systemic hyperlipidemia paradoxically underlies the fatty liver disease associated with chronic high-fat intake and obesity.

Original languageEnglish (US)
Pages (from-to)2501-2510
Number of pages10
JournalDiabetes
Volume56
Issue number10
DOIs
StatePublished - Oct 1 2007
Externally publishedYes

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High Fat Diet
Fatty Liver
Hyperlipidemias
Insulin Resistance
Homeostasis
Hepatocytes
Liver
Obesity
Paracrine Communication
Lipids
Glucose
Fibroblast Growth Factor Receptors
Obese Mice
White Adipose Tissue
Glucose Intolerance
Fibroblast Growth Factors
Hypercholesterolemia
Cell Communication
Liver Diseases
Research Design

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

FGFR4 prevents hyperlipidemia and insulin resistance but underlies high-fat diet-induced fatty liver. / Huang, Xinqiang; Yang, Chaofeng; Luo, Yongde; Jin, Chengliu; Wang, Fen; McKeehan, Wallace L.

In: Diabetes, Vol. 56, No. 10, 01.10.2007, p. 2501-2510.

Research output: Contribution to journalArticle

Huang, Xinqiang ; Yang, Chaofeng ; Luo, Yongde ; Jin, Chengliu ; Wang, Fen ; McKeehan, Wallace L. / FGFR4 prevents hyperlipidemia and insulin resistance but underlies high-fat diet-induced fatty liver. In: Diabetes. 2007 ; Vol. 56, No. 10. pp. 2501-2510.
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AU - Yang, Chaofeng

AU - Luo, Yongde

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AU - Wang, Fen

AU - McKeehan, Wallace L.

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N2 - OBJECTIVE - Fibroblast growth factor (FGF) family signaling largely controls cellular homeostasis through short-range inter-cell paracrine communication. Recently FGF15/19, 21, and 23 have been implicated in endocrine control of metabolic homeostasis. The identity and location of the FGF receptor isotypes that mediate these effects are unclear. The objective was to determine the role of FGFR4, an isotype that has been proposed to mediate an ileal FGF15/19 to hepatocyte FGFR4 axis in cholesterol homeostasis, in metabolic homeostasis in vivo. RESEARCH DESIGN AND METHODS - FGFR4-/- mice - mice overexpressing constitutively active hepatic FGFR4 - and FGFR4 -/- with constitutively active hepatic FGFR4 restored in the liver were subjected to a normal and a chronic high-fat diet sufficient to result in obesity. Systemic and liver-specific metabolic phenotypes were then characterized. RESULTS - FGFR4-deficient mice on a normal diet exhibited features of metabolic syndrome that include increased mass of white adipose tissue, hyperlipidemia, glucose intolerance, and insulin resistance, in addition to hypercholesterolemia. Surprisingly, the FGFR4 deficiency alleviated high-fat diet-induced fatty liver in obese mice, which is also a correlate of metabolic syndrome. Restoration of FGFR4, specifically in hepatocytes of FGFR4-deficient mice, decreased plasma lipid levels and restored the high-fat diet-induced fatty liver but failed to restore glucose tolerance and sensitivity to insulin. CONCLUSIONS - FGFR4 plays essential roles in systemic lipid and glucose homeostasis. FGFR4 activity in hepatocytes that normally serves to prevent systemic hyperlipidemia paradoxically underlies the fatty liver disease associated with chronic high-fat intake and obesity.

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