Liver-adipose tissue crosstalk in alcohol-associated liver disease: The role of mTOR ☆

Liver Research · 4 authors, 1 centre

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TL;DR

Using genetically modified mice, this preclinical study found that deleting the mTOR pathway specifically in adipocytes, but not the liver, exacerbated liver injury after acute alcohol exposure, highlighting the importance of adipose-liver crosstalk.

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Researchers created liver-specific and adipocyte-specific knockouts of Rptor and Mtor, along with double-deletion models, and subjected them to acute ethanol gavage. The central result was that adipocyte-specific, but not hepatocyte-specific, deletion of the mTOR pathway significantly exacerbated alcohol-induced liver injury, as evidenced by elevated serum alanine aminotransferase activities and increased hepatic inflammation and steatosis. This was associated with altered circulating adipokines, including increased pro-inflammatory cytokines and decreased fibroblast growth factor 21. The study is limited by its use of an acute binge model in mice, which may not fully recapitulate chronic human ALD, and the specific roles of individual adipokines require further dissection.

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other

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preclinical research

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AI pipeline

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ORIGINAL PAPER

PMC10134744

Liver-adipose tissue crosstalk in alcohol-associated liver disease: The role of mTOR ☆

Liver Research

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ABSTRACT

Abstract Background Alcohol-associated liver disease (ALD) is a major chronic liver disease around the world without successful treatment. Acute alcoholic hepatitis is one of the most severe forms of ALD with high mortality, which is often associated with binge drinking. Alcohol drinking dysregulates lipid metabolism, increases adipose tissue lipolysis, and induces liver steatosis and adipose tissue atrophy. Increasing evidence implicates that crosstalk of liver and adipose tissue in the pathogenesis of ALD. Mechanistic target of rapamycin (mTOR) is a phosphatidylinositol 3-kinase (PI3K)-like serine/threonine protein kinase that regulates lipid metabolism, cell proliferation and autophagy. However, the role of mTOR in regulating adipose-liver crosstalk in binge drinking-induced organ damage remains unclear. Methods We generated liver-specific and adipocyte-specific regulatory-associated protein of mTOR ( Rptor ) knockout ( Rptor LKO and Rptor AKO ) as well as Mtor knockout ( Mtor LKO and Mtor AKO ) mice, by crossing Rptor flox and Mtor flox mice with albumin Cre or adiponectin Cre mice, respectively. In addition, we generated liver and adipocyte double deletion of Rptor or Mtor ( Mtor L AKO and Rptor L AKO ) mice. The knockout mice with their matched wild-type littermates ( Rptor WT and Mtor WT ) were subjected to acute gavage of 7 g/kg ethanol. Results Mice with adipocyte deletion of Rptor or Mtor developed hepatomegaly and adipose tissue atrophy. Alcohol gavage increased liver injury, hepatic steatosis and inflammation in mouse livers as demonstrated by elevated serum alanine aminotransferase activities, increased hepatic levels of triglyceride and increased hepatic numbers of CD68 positive macrophages in mouse livers after alcohol gavage. Liver injury was further exacerbated by deletion of adipocyte Rptor or Mtor . Serum adipokine array analysis revealed that increased levels of pro-inflammatory cytokines IL-6 and TNFα as well as chemokine MCP-1 following acute alcohol gavage in wild-type mice, which were further increased in adipocyte-specific Mtor or Rptor knockout mice. Conversely, levels of anti-inflammatory cytokine IL-10 decreased in adipocyte-specific Mtor or Rptor knockout mice. The levels of circulating fibroblast growth factor 21 (FGF21) increased whereas levels of circulating adiponectin and fetuin A decreased in wild-type mice after alcohol gavage. Intriguingly, adipocyte-specific Mtor or Rptor knockout mice already had decreased basal level of FGF21 which increased by alcohol gavage. Moreover, adipocyte-specific Mtor or Rptor knockout mice already had increased basal level of adiponectin and decreased fetuin A which were not further changed by alcohol gavage. Conclusions Adipocyte but not hepatocyte ablation of Mtor pathway contributes to acute alcohol-induced liver injury with increased inflammation. Our results demonstrate the critical role of adipocyte mTOR in regulating the adipose-liver crosstalk in ALD. Keywords: Alcohol-associated liver disease (ALD), Liver injury, Mechanistic target of rapamycin (mTOR), Adipose atrophy, Adipokine, Liver-adipose tissue crosstalk

CITATION EXPORT

Yssa Rodriguez, Jack Dunfield, Tyson Roderique et al.. Liver-adipose tissue crosstalk in alcohol-associated liver disease: The role of mTOR☆. Liver Research. (2022). https://doi.org/10.1016/j.livres.2022.11.006

AUTHORS

4 · 1 CENTRES

Yssa Rodriguez, Jack Dunfield, Tyson Roderique, Hong-Min Ni

1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA