Targeting adipose tissue to tackle NASH: SPARCL1 as an emerging player
Robim M. Rodrigues, … , Yukun Guan, Bin Gao
Robim M. Rodrigues, … , Yukun Guan, Bin Gao
Published October 15, 2021
Citation Information: J Clin Invest. 2021;131(20):e153640. https://doi.org/10.1172/JCI153640.
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Commentary

Targeting adipose tissue to tackle NASH: SPARCL1 as an emerging player

Abstract

Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease, affecting 1.5%–6.5% of the world population. Currently, there are no FDA-approved drugs to treat this disease. Accumulating evidence suggests that metabolically hazardous visceral fat contributes to NASH progression by releasing fatty acids and proinflammatory mediators. Therefore, targeting adipose tissue to reduce adipose inflammation may provide an effective strategy to treat NASH. Another strategy is to target specific inflammatory mediators that are produced by adipose tissue and contribute to NASH progression. In this issue of the JCI, Liu, Xiang, et al. demonstrate that secreted protein acidic and rich in cysteine-like protein 1 (SPARCL1) was highly upregulated in adipose tissue and played a role in exacerbating NASH progression in a mouse model of NASH. Thus, inhibition of SPARCL1 may provide another attractive strategy to tackle NASH.

Authors

Robim M. Rodrigues, Yukun Guan, Bin Gao

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Figure 1

Adipose tissue inflammation promotes NASH progression via proinflammatory mediators, including SPARCL1.

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Adipose tissue inflammation promotes NASH progression via proinflammator...
Adipocyte hypertrophy during obesity can cause adipose tissue hypoxia and subsequent adipocyte death and adipose tissue inflammation, which further promote the recruitment of macrophages and neutrophils in adipose tissue. The infiltrated CCR2+ macrophages produce cytokines (such as TNF-α, IL-6, etc.) that perpetuate adipose tissue inflammation and promote hepatic macrophage infiltration (i) and liver inflammation. Recruitment of neutrophils in adipose tissue (ii), which is dependent on E-selectin, accelerates NASH progression by producing many inflammatory mediators (such as S100A8 and S100A9). In addition, adipose tissue inflammation activates adipocyte lipolysis to release free fatty acids (FFAs) (iii), leading to liver injury and inflammation. Finally, dysregulated adipose tissue can produce many proinflammatory mediators, including SPARCL1 (iv) whose function in NASH progression is reported by Liu, Xiang, et al. (22). Notably, SPARCL1 stimulates hepatocytes to produce CCL2 that induces hepatic macrophage recruitment and liver inflammation, thereby promoting NASH progression. Inhibition of SPARCL1 has therapeutic potential for the treatment of NASH.