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Overactivation of intestinal sterol response element-binding protein 2 promotes diet-induced nonalcoholic steatohepatitis.
Am J Physiol Gastrointest Liver Physiol. 2017 Nov 01; 313(5):G376-G385.AJ

Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver that may progress to hepatic fibrosis and nonalcoholic steatohepatitis (NASH). Mechanisms underlying NAFLD and NASH are not yet fully understood. Dietary cholesterol was recently shown to be a risk factor for the development of NASH, suggesting a role for intestinal handling of cholesterol. One important regulator of cholesterol homeostasis is the sterol response element-binding protein-2 (SREBP-2) transcription factor. We tested the hypothesis that the overactivation of intestinal SREBP-2 increases the susceptibility to diet-induced NASH. A transgenic mouse model with intestine-specific overexpression of active SREBP-2 (ISR2 mice) driven by villin promoter was used. ISR2 mice and their wild-type littermates were fed a regular chow diet or a high-fat, high-cholesterol (HFHC) diet (15% fat, 1% cholesterol) for 15 wk. Results showed that HFHC feeding to ISR2 mice caused hepatic inflammation with increased levels of proinflammatory cytokines. Histological examination demonstrated extensive fibrosis after a HFHC diet associated with a perivascular as well as pericellular collagen deposits in ISR2 mice compared with wild-type littermates. The severe hepatic inflammation and advanced fibrosis in ISR2 mice was not associated with a difference in lipid accumulation in ISR2 mice compared with wild type littermates after HFHC feeding. These data indicate that overactivation of intestinal SREBP2 promotes diet-induced hepatic inflammation with features of human NASH resulting in rapid severe fibrosis and provide a novel link between regulatory processes of intestinal cholesterol and progression of fatty liver.NEW & NOTEWORTHY The current study highlights the role of overactivation of intestinal SREBP-2 transcription factor in the progression of hepatic fibrosis associated with diet-induced NASH. Mice with intestine-specific overexpression of SREBP-2 demonstrated more inflammation and severe fibrosis in the liver in response to 15 wk of being fed a high-cholesterol, high-fat diet as compared with their wild-type littermates. These data demonstrate a novel link between intestinal regulatory processes of cholesterol metabolism and the pathogenesis of fatty liver diseases.

Authors+Show Affiliations

Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and.Rush University Medical Center, Chicago, Illinois.Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and.Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and.Rush University Medical Center, Chicago, Illinois.Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and.Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois. Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and.Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois. Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and.Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois; walrefai@uic.edu. Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28774869

Citation

Malhotra, Pooja, et al. "Overactivation of Intestinal Sterol Response Element-binding Protein 2 Promotes Diet-induced Nonalcoholic Steatohepatitis." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 313, no. 5, 2017, pp. G376-G385.
Malhotra P, Aloman C, Ankireddy A, et al. Overactivation of intestinal sterol response element-binding protein 2 promotes diet-induced nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2017;313(5):G376-G385.
Malhotra, P., Aloman, C., Ankireddy, A., Khadra, H., Ooka, K., Gill, R. K., Saksena, S., Dudeja, P. K., & Alrefai, W. A. (2017). Overactivation of intestinal sterol response element-binding protein 2 promotes diet-induced nonalcoholic steatohepatitis. American Journal of Physiology. Gastrointestinal and Liver Physiology, 313(5), G376-G385. https://doi.org/10.1152/ajpgi.00174.2017
Malhotra P, et al. Overactivation of Intestinal Sterol Response Element-binding Protein 2 Promotes Diet-induced Nonalcoholic Steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2017 Nov 1;313(5):G376-G385. PubMed PMID: 28774869.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overactivation of intestinal sterol response element-binding protein 2 promotes diet-induced nonalcoholic steatohepatitis. AU - Malhotra,Pooja, AU - Aloman,Costica, AU - Ankireddy,Aparna, AU - Khadra,Hani, AU - Ooka,Kohtaro, AU - Gill,Ravinder K, AU - Saksena,Seema, AU - Dudeja,Pradeep K, AU - Alrefai,Waddah A, Y1 - 2017/08/03/ PY - 2017/05/25/received PY - 2017/07/28/revised PY - 2017/07/28/accepted PY - 2017/8/5/pubmed PY - 2017/11/29/medline PY - 2017/8/5/entrez KW - ISR2 mice KW - high cholesterol KW - high fat KW - intestinal sterol response element-binding protein 2 KW - liver fibrosis KW - nonalcoholic fatty liver disease KW - nonalcoholic steatohepatitis SP - G376 EP - G385 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am. J. Physiol. Gastrointest. Liver Physiol. VL - 313 IS - 5 N2 - Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver that may progress to hepatic fibrosis and nonalcoholic steatohepatitis (NASH). Mechanisms underlying NAFLD and NASH are not yet fully understood. Dietary cholesterol was recently shown to be a risk factor for the development of NASH, suggesting a role for intestinal handling of cholesterol. One important regulator of cholesterol homeostasis is the sterol response element-binding protein-2 (SREBP-2) transcription factor. We tested the hypothesis that the overactivation of intestinal SREBP-2 increases the susceptibility to diet-induced NASH. A transgenic mouse model with intestine-specific overexpression of active SREBP-2 (ISR2 mice) driven by villin promoter was used. ISR2 mice and their wild-type littermates were fed a regular chow diet or a high-fat, high-cholesterol (HFHC) diet (15% fat, 1% cholesterol) for 15 wk. Results showed that HFHC feeding to ISR2 mice caused hepatic inflammation with increased levels of proinflammatory cytokines. Histological examination demonstrated extensive fibrosis after a HFHC diet associated with a perivascular as well as pericellular collagen deposits in ISR2 mice compared with wild-type littermates. The severe hepatic inflammation and advanced fibrosis in ISR2 mice was not associated with a difference in lipid accumulation in ISR2 mice compared with wild type littermates after HFHC feeding. These data indicate that overactivation of intestinal SREBP2 promotes diet-induced hepatic inflammation with features of human NASH resulting in rapid severe fibrosis and provide a novel link between regulatory processes of intestinal cholesterol and progression of fatty liver.NEW & NOTEWORTHY The current study highlights the role of overactivation of intestinal SREBP-2 transcription factor in the progression of hepatic fibrosis associated with diet-induced NASH. Mice with intestine-specific overexpression of SREBP-2 demonstrated more inflammation and severe fibrosis in the liver in response to 15 wk of being fed a high-cholesterol, high-fat diet as compared with their wild-type littermates. These data demonstrate a novel link between intestinal regulatory processes of cholesterol metabolism and the pathogenesis of fatty liver diseases. SN - 1522-1547 UR - https://www.unboundmedicine.com/medline/citation/28774869/Overactivation_of_intestinal_sterol_response_element_binding_protein_2_promotes_diet_induced_nonalcoholic_steatohepatitis_ L2 - http://www.physiology.org/doi/full/10.1152/ajpgi.00174.2017?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -