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Farnesoid X Receptor Deficiency Induces Hepatic Lipid and Glucose Metabolism Disorder via Regulation of Pyruvate

Wenyi Deng1,2, Wenjing Fan3, Tingting Tang1

  • 1Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan, China 421001.

Oxidative Medicine and Cellular Longevity
|March 7, 2022
PubMed

Insights

Farnesoid X receptor (FXR) deficiency impairs lipid and glucose metabolism, leading to nonalcoholic fatty liver disease (NAFLD). FXR regulates this balance via pyruvate dehydrogenase kinase 4 (PDK4).

Area of Science:

  • Metabolic disease research
  • Hepatology
  • Molecular endocrinology

Background:

  • Farnesoid X receptor (FXR) is a bile acid receptor crucial for lipid, glucose, and energy homeostasis.
  • FXR agonists are explored for treating nonalcoholic fatty liver disease (NAFLD), but mechanisms are unclear.
  • FXR's role in NAFLD pathogenesis requires further elucidation.

Purpose of the Study:

  • To investigate the role of FXR in NAFLD pathogenesis and its underlying molecular mechanisms.
  • To determine if FXR regulates glucose and lipid metabolism through pyruvate dehydrogenase kinase 4 (PDK4).

Main Methods:

  • Utilized FXR-null mice fed normal or high-fat diets to model NAFLD.
  • Performed transcriptomic analysis to identify key metabolic regulators.
  • Investigated PDK4 expression in FXR knockout cells and hepatocytes.
  • Assessed the effect of PDK4 inhibition on lipid accumulation in vivo and in vitro.

Main Results:

  • FXR-null mice exhibited hallmark NAFLD features: hepatomegaly, steatosis, hepatic lipid droplet accumulation, glucose intolerance, and dyslipidemia.
  • Transcriptomic analysis revealed upregulated lipid synthesis and glucose metabolism-related proteins in FXR-null mice.
  • PDK4 expression was significantly increased in FXR-deficient conditions.
  • Inhibition of PDK4 ameliorated hepatic lipid accumulation in FXR-deficient models.

Conclusions:

  • FXR acts as a nuclear transcription factor regulating glucose and lipid metabolism balance.
  • FXR exerts its metabolic control, in part, through the regulation of PDK4.
  • These findings offer insights into the therapeutic mechanisms of FXR agonists for metabolic diseases like NAFLD.

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