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 February 1, 2017; First published January 17, 2017
Citation Information: J Clin Invest. 2017;127(2):583-592. https://doi.org/10.1172/JCI85499.
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Categories: 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 1

LRH-1 K289R mice display increased de novo lipogenesis.

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LRH-1 K289R mice display increased de novo lipogenesis. (A) Heat map sho...
(A) Heat map showing the expression of genes involved in de novo fatty acid and cholesterol synthesis in refed WT and K289R mice. Normalized expression values are in log2 scale. SREBP-1, depicting mainly SREBP-1 target genes; SREBP-2, mostly SREBP-2 target genes; NS, transcripts that are not significantly changed between the indicated genotypes. For all other transcripts P < 0.05. (B) Hepatic mRNA expression of Srebf1 in K289R and WT mice. n = 10 per genotype. (C) Left, immunoblots of precursor and cleaved (cl) SREBP-1, SCD1, HSP90, and P62 in hepatic lysates of WT or K289R livers. Right, graph displaying the ratio of cleaved to precursor SREBP-1. (D) Representative images of liver sections of K289R or WT mice stained with oil red O to visualize neutral lipids. Scale bar: 200 μm. (E) Quantification of hepatic triglyceride content in WT and K289R mice. n = 10 per group. (F and G) Plasma triglyceride (TG) and free fatty acid (FFA) contents in WT and K289R mice. n = 10 per group. (H–J) Fractional de novo synthesis rates of palmitate (H), stearate (I), and oleate (J) in WT and K289R mice. n = 6 per group. Error bars represent mean ± SEM. *P < 0.05, **P < 0.01 relative to WT within each nutritional state; §P < 0.001 refed relative to fasted mice, as determined by unpaired Student’s t test (A) or 2-way ANOVA with Bonferroni’s post-hoc test (B, C, E–J). WT, LRH-1 WT; K289R, LRH-1 K289R mice.