Hepatocyte Adenosine Kinase Promotes Excessive Fat Deposition and Liver Inflammation

Gastroenterology. 2023 Jan;164(1):134-146. doi: 10.1053/j.gastro.2022.09.027. Epub 2022 Sep 28.

Abstract

Background & aims: Nonalcoholic fatty liver disease is highly associated with obesity and progresses to nonalcoholic steatohepatitis when the liver develops overt inflammatory damage. While removing adenosine in the purine salvage pathway, adenosine kinase (ADK) regulates methylation reactions. We aimed to study whether hepatocyte ADK functions as an obesogenic gene/enzyme to promote excessive fat deposition and liver inflammation.

Methods: Liver sections of human subjects were examined for ADK expression using immunohistochemistry. Mice with hepatocyte-specific ADK disruption or overexpression were examined for hepatic fat deposition and inflammation. Liver lipidomics, hepatocyte RNA sequencing (RNA-seq), and single-cell RNA-seq for liver nonparenchymal cells were performed to analyze ADK regulation of hepatocyte metabolic responses and hepatocyte-nonparenchymal cells crosstalk.

Results: Whereas patients with nonalcoholic fatty liver disease had increased hepatic ADK levels, mice with hepatocyte-specific ADK disruption displayed decreased hepatic fat deposition on a chow diet and were protected from diet-induced excessive hepatic fat deposition and inflammation. In contrast, mice with hepatocyte-specific ADK overexpression displayed increased body weight and adiposity and elevated degrees of hepatic steatosis and inflammation compared with control mice. RNA-seq and epigenetic analyses indicated that ADK increased hepatic DNA methylation and decreased hepatic Ppara expression and fatty acid oxidation. Lipidomic and single-cell RNA-seq analyses indicated that ADK-driven hepatocyte factors, due to mitochondrial dysfunction, enhanced macrophage proinflammatory activation in manners involving increased expression of stimulator of interferon genes.

Conclusions: Hepatocyte ADK functions to promote excessive fat deposition and liver inflammation through suppressing hepatocyte fatty acid oxidation and producing hepatocyte-derived proinflammatory mediators. Therefore, hepatocyte ADK is a therapeutic target for managing obesity and nonalcoholic fatty liver disease.

Keywords: Insulin Resistance; Mitochondrial DNA.

MeSH terms

  • Adenosine Kinase / genetics
  • Adenosine Kinase / metabolism
  • Animals
  • Diet, High-Fat
  • Fatty Acids / metabolism
  • Hepatitis* / metabolism
  • Hepatocytes / metabolism
  • Humans
  • Inflammation / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease* / genetics
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Obesity / metabolism

Substances

  • Adenosine Kinase
  • Fatty Acids