Simon Y, Kessler SM, Gemperlein K, Bohle RM, Müller R, Haybaeck J, Kiemer AK. Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis. World J Gastroenterol 2014; 20(47): 17839-17850 [PMID: 25548482 DOI: 10.3748/wjg.v20.i47.17839]
Corresponding Author of This Article
Alexandra K Kiemer, PhD, Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 2, 66123 Saarbrücken, Germany. pharm.bio.kiemer@mx.uni-saarland.de
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Original Article
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World J Gastroenterol. Dec 21, 2014; 20(47): 17839-17850 Published online Dec 21, 2014. doi: 10.3748/wjg.v20.i47.17839
Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis
Yvette Simon, Sonja M Kessler, Katja Gemperlein, Rainer M Bohle, Rolf Müller, Johannes Haybaeck, Alexandra K Kiemer
Yvette Simon, Sonja M Kessler, Alexandra K Kiemer, Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66123 Saarbrücken, Germany
Sonja M Kessler, Johannes Haybaeck, Medical University of Graz, Institute of Pathology, Graz 8036, Austria
Katja Gemperlein, Rolf Müller, Department of Pharmacy, Pharmaceutical Biotechnology, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), 66123 Saarbrücken, Germany
Rainer M Bohle, Saarland University, Department of Pathology, 66421 Homburg, Germany
Author contributions: Simon Y and Kessler SM contributed equally to this paper; Simon Y, Kessler SM, Haybaeck J and Kiemer AK designed the experiments, analyzed the data and wrote the manuscript; Kiemer AK initiated and directed the study; Kessler SM, Bohle RM and Haybaeck J scored the histological slides; Gemperlein K and Müller R performed GC-MS lipid analyses; all authors had full access to all of the data (including statistical reports and tables) in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Supported by An EASL Sheila Sherlock fellowship and a Bank Austria visiting scientist program fellowship (to Kessler SM)
Correspondence to: Alexandra K Kiemer, PhD, Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 2, 66123 Saarbrücken, Germany. pharm.bio.kiemer@mx.uni-saarland.de
Telephone: +49-681-30257301 Fax: +49-681-30257302
Received: April 11, 2014 Revised: June 15, 2014 Accepted: July 11, 2014 Published online: December 21, 2014 Processing time: 252 Days and 23 Hours
Core Tip
Core tip: Dietary cholesterol represents a critical factor for the development of non-alcoholic steatohepatitis (NASH) from steatosis. Liver-specific overexpression of the insulin-like growth factor 2 mRNA binding protein p62/IMP2-2/IGF2BP2-2 induces steatosis and amplifies NASH-induced fibrosis. Here, we show that p62 elevates monounsaturated fatty acids and hepatic cholesterol in the absence of exogenous cholesterol. Filipin staining demonstrates increased free cholesterol in p62 transgenic livers. Srebf2-induced cholesterol biosynthesis in transgenics is most likely due to pronounced hepatic iron accumulation, which is also associated with lipid peroxidation in transgenic livers. In summary, p62/IGF2BP2-2 drives the progression of NASH by increasing hepatic free cholesterol.
