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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\u2013containing 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.<\/jats:p>","DOI":"10.1172\/jci.insight.154940","type":"journal-article","created":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T12:02:03Z","timestamp":1675771323000},"source":"Crossref","is-referenced-by-count":16,"title":["Adipose-targeted SWELL1 deletion exacerbates obesity- and age-related nonalcoholic fatty liver disease"],"prefix":"10.1172","volume":"8","author":[{"given":"Susheel K.","family":"Gunasekar","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Heebink","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. 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