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Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice.
J Lipid Res. 2011 Sep; 52(9):1626-35.JL

Abstract

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver disease. Mechanisms that underlie this progression remain poorly understood, partly due to lack of good animal models that resemble human NASH. We previously showed that several metabolic syndrome features that develop in LDL receptor-deficient (LDLR-/-) mice fed a diabetogenic diet are worsened by dietary cholesterol. To test whether dietary cholesterol can alter the hepatic phenotype in the metabolic syndrome, we fed LDLR-/- mice a high-fat, high-carbohydrate diabetogenic diet (DD) without or with added cholesterol (DDC). Both groups of mice developed obesity and insulin resistance. Hyperinsulinemia, dyslipidemia, hepatic triglyceride, and alanine aminotransferase (ALT) elevations were greater with DDC. Livers of DD-fed mice showed histological changes resembling NAFLD, including steatosis and modest fibrotic changes; however, DDC-fed animals developed micro- and macrovesicular steatosis, inflammatory cell foci, and fibrosis resembling human NASH. Dietary cholesterol also exacerbated hepatic macrophage infiltration, apoptosis, and oxidative stress. Thus, LDLR-/- mice fed diabetogenic diets may be useful models for studying human NASH. Dietary cholesterol appears to confer a second "hit" that results in a distinct hepatic phenotype characterized by increased inflammation and oxidative stress.

Authors+Show Affiliations

Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21690266

Citation

Subramanian, Savitha, et al. "Dietary Cholesterol Exacerbates Hepatic Steatosis and Inflammation in Obese LDL Receptor-deficient Mice." Journal of Lipid Research, vol. 52, no. 9, 2011, pp. 1626-35.
Subramanian S, Goodspeed L, Wang S, et al. Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice. J Lipid Res. 2011;52(9):1626-35.
Subramanian, S., Goodspeed, L., Wang, S., Kim, J., Zeng, L., Ioannou, G. N., Haigh, W. G., Yeh, M. M., Kowdley, K. V., O'Brien, K. D., Pennathur, S., & Chait, A. (2011). Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice. Journal of Lipid Research, 52(9), 1626-35. https://doi.org/10.1194/jlr.M016246
Subramanian S, et al. Dietary Cholesterol Exacerbates Hepatic Steatosis and Inflammation in Obese LDL Receptor-deficient Mice. J Lipid Res. 2011;52(9):1626-35. PubMed PMID: 21690266.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice. AU - Subramanian,Savitha, AU - Goodspeed,Leela, AU - Wang,Shari, AU - Kim,Jinkyu, AU - Zeng,Lixia, AU - Ioannou,George N, AU - Haigh,W Geoffrey, AU - Yeh,Matthew M, AU - Kowdley,Kris V, AU - O'Brien,Kevin D, AU - Pennathur,Subramaniam, AU - Chait,Alan, Y1 - 2011/06/20/ PY - 2011/6/22/entrez PY - 2011/6/22/pubmed PY - 2012/3/1/medline SP - 1626 EP - 35 JF - Journal of lipid research JO - J. Lipid Res. VL - 52 IS - 9 N2 - Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver disease. Mechanisms that underlie this progression remain poorly understood, partly due to lack of good animal models that resemble human NASH. We previously showed that several metabolic syndrome features that develop in LDL receptor-deficient (LDLR-/-) mice fed a diabetogenic diet are worsened by dietary cholesterol. To test whether dietary cholesterol can alter the hepatic phenotype in the metabolic syndrome, we fed LDLR-/- mice a high-fat, high-carbohydrate diabetogenic diet (DD) without or with added cholesterol (DDC). Both groups of mice developed obesity and insulin resistance. Hyperinsulinemia, dyslipidemia, hepatic triglyceride, and alanine aminotransferase (ALT) elevations were greater with DDC. Livers of DD-fed mice showed histological changes resembling NAFLD, including steatosis and modest fibrotic changes; however, DDC-fed animals developed micro- and macrovesicular steatosis, inflammatory cell foci, and fibrosis resembling human NASH. Dietary cholesterol also exacerbated hepatic macrophage infiltration, apoptosis, and oxidative stress. Thus, LDLR-/- mice fed diabetogenic diets may be useful models for studying human NASH. Dietary cholesterol appears to confer a second "hit" that results in a distinct hepatic phenotype characterized by increased inflammation and oxidative stress. SN - 1539-7262 UR - https://www.unboundmedicine.com/medline/citation/21690266/Dietary_cholesterol_exacerbates_hepatic_steatosis_and_inflammation_in_obese_LDL_receptor_deficient_mice_ L2 - http://www.jlr.org/cgi/pmidlookup?view=long&pmid=21690266 DB - PRIME DP - Unbound Medicine ER -