Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease
Sokrates Stein, … , Maaike H. Oosterveer, Kristina Schoonjans
Sokrates Stein, … , Maaike H. Oosterveer, Kristina Schoonjans
Published January 17, 2017
Citation Information: J Clin Invest. 2017;127(2):583-592. https://doi.org/10.1172/JCI85499.
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Research Article Hepatology Metabolism

Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease

Abstract

Hepatic steatosis is caused by metabolic imbalances that could be explained in part by an increase in de novo lipogenesis that results from increased sterol element binding protein 1 (SREBP-1) activity. The nuclear receptor liver receptor homolog 1 (LRH-1) is an important regulator of intermediary metabolism in the liver, but its role in regulating lipogenesis is not well understood. Here, we have assessed the contribution of LRH-1 SUMOylation to the development of nonalcoholic fatty liver disease (NAFLD). Mice expressing a SUMOylation-defective mutant of LRH-1 (LRH-1 K289R mice) developed NAFLD and early signs of nonalcoholic steatohepatitis (NASH) when challenged with a lipogenic, high-fat, high-sucrose diet. Moreover, we observed that the LRH-1 K289R mutation induced the expression of oxysterol binding protein-like 3 (OSBPL3), enhanced SREBP-1 processing, and promoted de novo lipogenesis. Mechanistically, we demonstrated that ectopic expression of OSBPL3 facilitates SREBP-1 processing in WT mice, while silencing hepatic Osbpl3 reverses the lipogenic phenotype of LRH-1 K289R mice. These findings suggest that compromised SUMOylation of LRH-1 promotes the development of NAFLD under lipogenic conditions through regulation of OSBPL3.

Authors

Sokrates Stein, Vera Lemos, Pan Xu, Hadrien Demagny, Xu Wang, Dongryeol Ryu, Veronica Jimenez, Fatima Bosch, Thomas F. Lüscher, Maaike H. Oosterveer, Kristina Schoonjans

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Figure 5

LRH-1 K289R mice display increased inflammation and early signs of fibrosis upon HFHS diet feeding.

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LRH-1 K289R mice display increased inflammation and early signs of fibro...
(A) Representative images of liver sections of K289R or WT mice stained with sirius red or CD45 to visualize collagen depositions and CD45-positive cells, respectively. Scale bars: 200 μm. CV, central vein. (B–E) Hepatic mRNA expression of genes involved in inflammation (B), matrix degradation (C), fibrosis (D), and stellate cells (E) in K289R and WT mice. n = 9 per genotype. (F) Graphical presentation showing how the LRH-1/OSBPL3 axis drives the accumulation of hepatic lipids. Error bars represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 relative to WT within each diet, as determined by 2-way ANOVA with Bonferroni’s post-hoc test (B–E).