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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.

SUBMITTER: Stein S 

PROVIDER: S-EPMC5272172 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Stein Sokrates S   Lemos Vera V   Xu Pan P   Demagny Hadrien H   Wang Xu X   Ryu Dongryeol D   Jimenez Veronica V   Bosch Fatima F   Lüscher Thomas F TF   Oosterveer Maaike H MH   Schoonjans Kristina K  

The Journal of clinical investigation 20170117 2


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 disea  ...[more]

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