Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Adipose-targeted SWELL1 deletion exacerbates obesity- and age-related nonalcoholic fatty liver disease
Susheel K. Gunasekar, … , Joel D. Schilling, Rajan Sah
Susheel K. Gunasekar, … , Joel D. Schilling, Rajan Sah
Published February 7, 2023
Citation Information: JCI Insight. 2023;8(5):e154940. https://doi.org/10.1172/jci.insight.154940.
View: Text | PDF
Research Article Hepatology Metabolism

Adipose-targeted SWELL1 deletion exacerbates obesity- and age-related nonalcoholic fatty liver disease

  • Text
  • PDF
Abstract

Healthy expansion of adipose tissue is critical for the maintenance of metabolic health, providing an optimized reservoir for energy storage in the form of triacylglycerol-rich lipoproteins. Dysfunctional adipocytes that are unable to efficiently store lipid can result in lipodystrophy and contribute to nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. Leucine-rich repeat containing protein 8a/SWELL1 functionally encodes the volume-regulated anion channel complex in adipocytes, is induced in early obesity, and is required for normal adipocyte expansion during high-fat feeding. Adipose-specific SWELL1 ablation (Adipo KO) leads to insulin resistance and hyperglycemia during caloric excess, both of which are associated with NAFLD. Here, we show that Adipo-KO mice exhibited impaired adipose depot expansion and excess lipolysis when raised on a variety of high-fat diets, resulting in increased diacylglycerides and hepatic steatosis, thereby driving liver injury. Liver lipidomic analysis revealed increases in oleic acid–containing hepatic triacylglycerides and injurious hepatic diacylglyceride species, with reductions in hepatocyte-protective phospholipids and antiinflammatory free fatty acids. Aged Adipo-KO mice developed hepatic steatosis on a regular chow diet, and Adipo-KO male mice developed spontaneous, aggressive hepatocellular carcinomas (HCCs). These data highlight the importance of adipocyte SWELL1 for healthy adipocyte expansion to protect against NAFLD and HCC in the setting of overnutrition and with aging.

Authors

Susheel K. Gunasekar, John Heebink, Danielle H. Carpenter, Ashutosh Kumar, Litao Xie, Haixia Zhang, Joel D. Schilling, Rajan Sah

×

Full Text PDF | Download (16.22 MB)


Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts