Adipose-targeted SWELL1 deletion exacerbates obesity- and age-related nonalcoholic fatty liver disease
Susheel K. Gunasekar, John Heebink, Danielle H. Carpenter, Ashutosh Kumar, Litao Xie, Haixia Zhang, Joel D. Schilling, Rajan Sah
Susheel K. Gunasekar, John Heebink, Danielle H. Carpenter, Ashutosh Kumar, Litao Xie, Haixia Zhang, Joel D. Schilling, Rajan Sah
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Research Article Hepatology Metabolism

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

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

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Figure 3

Adipose SWELL1 deletion predisposes to developing NAFLD with overnutrition.

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Adipose SWELL1 deletion predisposes to developing NAFLD with overnutriti...
(A) Representative images of liver dissected from WT (top) and Adipo-KO (bottom) mice (males) fed with HFHS diet for 27 weeks. (B) Total liver mass and ratio of liver mass over body weight of WT and Adipo-KO mice from A. (C) Representative images of H&E-stained liver sections of WT and Adipo-KO mice (Scale bar: 100 μm). (D) Micro- and macrovesicular fat regions along with the mononuclear inflammatory cells (solid black circles) in WT and Adipo-KO mice (20× objective, 200× magnification). (E) Liver steatosis (%area) estimated from H&E-stained liver sections in C of WT (n = 2, 17 ROIs) and Adipo-KO (n = 2, 21 ROIs) mice using ImageJ software (NIH). (F) mRNA expression of PPARG in WT (n = 6) and Adipo-KO (n = 4) livers relative to control GAPDH. (G) mRNA expression of CD68 in WT (n = 6) and Adipo-KO (n = 4) livers relative to control GAPDH. (H) Total liver mass and ratio of liver mass over body weight of WT (n = 8) and Adipo-KO (n = 9) mice (males) fed with GAN diet for 23–25 weeks. (I) Measurement for total diacylglycerides (DAGs) from WT (n = 8) and Adipo-KO (n = 9) livers in H. (J) Representative images of H&E-stained liver sections of GAN diet–fed WT and Adipo-KO mice in H indicating cells that are normal (blue) and with hepatocellular hypertrophy (black outline) (40× objective). (K and L) Cumulative steatosis score (K) derived from macrovesicular, microvesicular, and hepatocellular hypertrophy scores (L) of liver sections from GAN diet–fed WT and Adipo-KO (n = 9 each) mice. Data are represented as mean ± SEM. Two-tailed unpaired t test was used in B, E–I, K, and L where *, **, and *** represent P < 0.05, P < 0.01, and P < 0.001, respectively. ROIs, regions of interest.