UCP1 governs liver extracellular succinate and inflammatory pathogenesis

Nat Metab. 2021 May;3(5):604-617. doi: 10.1038/s42255-021-00389-5. Epub 2021 May 17.

Abstract

Non-alcoholic fatty liver disease (NAFLD), the most prevalent liver pathology worldwide, is intimately linked with obesity and type 2 diabetes. Liver inflammation is a hallmark of NAFLD and is thought to contribute to tissue fibrosis and disease pathogenesis. Uncoupling protein 1 (UCP1) is exclusively expressed in brown and beige adipocytes, and has been extensively studied for its capacity to elevate thermogenesis and reverse obesity. Here we identify an endocrine pathway regulated by UCP1 that antagonizes liver inflammation and pathology, independent of effects on obesity. We show that, without UCP1, brown and beige fat exhibit a diminished capacity to clear succinate from the circulation. Moreover, UCP1KO mice exhibit elevated extracellular succinate in liver tissue that drives inflammation through ligation of its cognate receptor succinate receptor 1 (SUCNR1) in liver-resident stellate cell and macrophage populations. Conversely, increasing brown and beige adipocyte content in mice antagonizes SUCNR1-dependent inflammatory signalling in the liver. We show that this UCP1-succinate-SUCNR1 axis is necessary to regulate liver immune cell infiltration and pathology, and systemic glucose intolerance in an obesogenic environment. As such, the therapeutic use of brown and beige adipocytes and UCP1 extends beyond thermogenesis and may be leveraged to antagonize NAFLD and SUCNR1-dependent liver inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adipose Tissue, Beige / metabolism
  • Adipose Tissue, White / metabolism
  • Animals
  • Disease Susceptibility*
  • Extracellular Space / metabolism
  • Glucose / metabolism
  • Glucose Intolerance / metabolism
  • Hepatitis / etiology*
  • Hepatitis / metabolism*
  • Hepatitis / pathology
  • Humans
  • Metabolic Networks and Pathways
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Succinic Acid / metabolism*
  • Uncoupling Protein 1 / genetics*
  • Uncoupling Protein 1 / metabolism

Substances

  • Receptors, G-Protein-Coupled
  • SUCNR1 protein, human
  • Uncoupling Protein 1
  • Succinic Acid
  • Glucose