title: 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.forename: Sokrates
authors.initials: S
authors.lastname: Stein
authors.forename: Vera
authors.initials: V
authors.lastname: Lemos
authors.forename: Pan
authors.initials: P
authors.lastname: Xu
authors.forename: Hadrien
authors.initials: H
authors.lastname: Demagny
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.forename: Veronica
authors.initials: V
authors.lastname: Jimenez
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Maaike H
authors.initials: MH
authors.lastname: Oosterveer
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004040:Dietary Carbohydrates / Q000009:adverse effects / Q000494:pharmacology; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D058207:Sumoylation
chemical_list: D002352:Carrier Proteins; D004040:Dietary Carbohydrates; D004041:Dietary Fats; C431936:Nr5a2 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1