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 2

Osbpl3 is a direct LRH-1 target gene and overexpressed in LRH-1 K289R mice.

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Osbpl3 is a direct LRH-1 target gene and overexpressed in LRH-1 K289R m...
(A) Heat map showing the hepatic expression of oxysterol-binding protein family members in WT and K289R mice. Normalized expression values are in log2 scale. (B and C) Expression of Osbpl3 mRNA in hepatic lysates of fasted and refed WT and K289R mice (B) and the fold change between the genotypes (C). n = 4 per fasted, 2-hour–, or 12-hour–refed groups, and n = 5 per 6-hour–refed groups. (D) Expression levels of OSBPL3 protein in hepatic lysates of fasted and refed WT and K289R mice. (E) Schematic showing the genomic area containing the Osbpl3 gene and the sites used for ChIP-qPCR experiments (mouse genome assembly mm10). (F and G) Binding of LRH-1 to the different Osbpl3 promoter sites assessed by ChIP analysis using genomic DNA from fasted WT (F) and refed WT livers (G). n = 5 WT fasted, n = 5 WT refed. Error bars represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, §P = 2 × 10–7 relative to WT, as determined by unpaired Student’s t test (A), or 1-way (C) or 2-way (B, F, G) ANOVA with Bonferroni post-hoc test. TSS, transcription start site.