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 4

LRH-1 K289R mice develop NAFLD upon HFHS diet feeding.

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LRH-1 K289R mice develop NAFLD upon HFHS diet feeding. (A) Representativ...
(A) Representative images of liver sections of K289R or WT mice stained with H&E or oil red O to visualize the tissue structure and neutral lipids, respectively. Black scale bar: 200 μm; white scale bar: 50 μm. (B and C) Quantification of triglyceride content in plasma (B) and in hepatic lipid extracts (C) in WT and K289R mice. WT, n = 7; K289R, n = 10. (D and E) Plasma levels of ALAT (D) and ASAT (E) in mice fed a HFHS diet. WT, n = 7; K289R, n = 10. (F and G) Expression of Osbpl3 mRNA (F) and protein (G) levels in livers of WT and K289R mice fed chow and HFHS diets. n = 9 per genotype. (H) Heat map displaying the expression of Osbpl3 as well as markers of matrix degradation, fibrosis, and inflammation in mice that were classified as LFL responders, LFH responders, HFL responders, and HFH responders according to the development of NAFLD/NASH upon chow or high-fat diet feeding (24). (I) Expression of OSBPL3 and markers of matrix degradation, fibrosis, and inflammation in transcriptomic data from human patients that were categorized for mild or advanced NAFLD (25). Normalized expression values are in log2 scale. Error bars represent mean ± SEM. **P < 0.01, ***P < 0.001 relative to WT; §P < 0.001 refed relative to fasted mice, as determined by unpaired Student’s t test (B, D, E) or 2-way ANOVA with Bonferroni’s post-hoc test (C, F).