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Title: HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPAR{gamma}

Abstract

Hepatic steatosis is a common feature in patients with chronic hepatitis C virus (HCV) infection. HCV core protein plays an important role in the development of hepatic steatosis in HCV infection. Because SREBP1 (sterol regulatory element binding protein 1) and PPAR{gamma} (peroxisome proliferators-activated receptor {gamma}) are involved in the regulation of lipid metabolism of hepatocyte, we sought to determine whether HCV core protein may impair the expression and activity of SREBP1 and PPAR{gamma}. In this study, it was demonstrated that HCV core protein increases the gene expression of SREBP1 not only in Chang liver, Huh7, and HepG2 cells transiently transfected with HCV core protein expression plasmid, but also in Chang liver-core stable cells. Furthermore, HCV core protein enhanced the transcriptional activity of SREBP1. In addition, HCV core protein elevated PPAR{gamma} transcriptional activity. However, HCV core protein had no effect on PPAR{gamma} gene expression. Finally, we showed that HCV core protein stimulates the genes expression of lipogenic enzyme and fatty acid uptake associated protein. Therefore, our finding provides a new insight into the mechanism of hepatic steatosis by HCV infection.

Authors:
 [1];  [1];  [1];  [1];  [2];  [3]
  1. Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735 (Korea, Republic of)
  2. Department of Internal Medicine, Bongseng Memorial Hospital, Busan 601-723 (Korea, Republic of)
  3. Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735 (Korea, Republic of). E-mail: molecule85@pusan.ac.kr
Publication Date:
OSTI Identifier:
20979881
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 355; Journal Issue: 4; Other Information: DOI: 10.1016/j.bbrc.2007.02.044; PII: S0006-291X(07)00298-7; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARBOXYLIC ACIDS; ENZYMES; GENE REGULATION; GENES; HEPATITIS; LIPIDS; LIVER; METABOLISM; PATIENTS; RECEPTORS; STEROLS; VIRUSES

Citation Formats

Kim, Kook Hwan, Hong, Sung Pyo, Kim, KyeongJin, Park, Min Jung, Kim, Kwang Jin, and Cheong, JaeHun. HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPAR{gamma}. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2007.02.044.
Kim, Kook Hwan, Hong, Sung Pyo, Kim, KyeongJin, Park, Min Jung, Kim, Kwang Jin, & Cheong, JaeHun. HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPAR{gamma}. United States. doi:10.1016/j.bbrc.2007.02.044.
Kim, Kook Hwan, Hong, Sung Pyo, Kim, KyeongJin, Park, Min Jung, Kim, Kwang Jin, and Cheong, JaeHun. Fri . "HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPAR{gamma}". United States. doi:10.1016/j.bbrc.2007.02.044.
@article{osti_20979881,
title = {HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPAR{gamma}},
author = {Kim, Kook Hwan and Hong, Sung Pyo and Kim, KyeongJin and Park, Min Jung and Kim, Kwang Jin and Cheong, JaeHun},
abstractNote = {Hepatic steatosis is a common feature in patients with chronic hepatitis C virus (HCV) infection. HCV core protein plays an important role in the development of hepatic steatosis in HCV infection. Because SREBP1 (sterol regulatory element binding protein 1) and PPAR{gamma} (peroxisome proliferators-activated receptor {gamma}) are involved in the regulation of lipid metabolism of hepatocyte, we sought to determine whether HCV core protein may impair the expression and activity of SREBP1 and PPAR{gamma}. In this study, it was demonstrated that HCV core protein increases the gene expression of SREBP1 not only in Chang liver, Huh7, and HepG2 cells transiently transfected with HCV core protein expression plasmid, but also in Chang liver-core stable cells. Furthermore, HCV core protein enhanced the transcriptional activity of SREBP1. In addition, HCV core protein elevated PPAR{gamma} transcriptional activity. However, HCV core protein had no effect on PPAR{gamma} gene expression. Finally, we showed that HCV core protein stimulates the genes expression of lipogenic enzyme and fatty acid uptake associated protein. Therefore, our finding provides a new insight into the mechanism of hepatic steatosis by HCV infection.},
doi = {10.1016/j.bbrc.2007.02.044},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 355,
place = {United States},
year = {Fri Apr 20 00:00:00 EDT 2007},
month = {Fri Apr 20 00:00:00 EDT 2007}
}
  • Macroautophagy, or autophagy, is a cellular response in which unnecessary cytoplasmic components, including lipids and organelles, are self-degraded. Recent studies closely related autophagy to activation of hepatic stellate cells (HSCs), a process critical in the pathogenesis of liver fibrosis. During HSC activation, cytoplasmic lipid droplets (LDs) are degraded as autophagic cargo, and then cells express fibrogenic genes. Thus, inhibition of autophagy in HSCs is a potential therapeutic approach for attenuating liver fibrosis. We found that tetrandrine, a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra, induced lipid accumulation, a phenotype associated with quiescent HSCs, through blockade of autophagy in the rat-derived HSCmore » line HSC-T6. Tetrandrine inhibited autophagic flux without affecting lysosomal function. A phenotypic comparison using siRNA knockdown suggested that tetrandrine may target regulators, involved in fusion between autophagosomes and lysosomes (e.g., syntaxin 17). Moreover, perilipin 1, an LD-coated protein, co-localized specifically with LC3, a marker protein for autophagosomes, in tetrandrine-treated HSC-T6 cells. This suggests a potential role for perilipin 1 in autophagy-mediated LD degradation in HSCs. Our results identified tetrandrine as a potential tool for prevention and treatment of HSC activation. - Highlights: • Autophagy is closely related to lipid degradation in hepatic stellate cells. • Tetrandrine (Tet) causes lipid accumulation via blockade of autophagy in HSC-T6 cells. • Tet blocked autophagy without affecting lysosomal function unlike bafilomycin A{sub 1}. • Perilipin 1 was specifically co-localized with LC3 in Tet-treated cells. • Perilipin 1 may play potential roles in autophagy-mediated lipid degradation.« less
  • Patients with long-lasting hepatitis C virus (HCV) infection are at major risk of hepatocellular carcinoma (HCC). Iron accumulation in the livers of these patients is thought to exacerbate conditions of oxidative stress. Transgenic mice that express the HCV core protein develop HCC after the steatosis stage and produce an excess of hepatic reactive oxygen species (ROS). The overproduction of ROS in the liver is the net result of HCV core protein-induced dysfunction of the mitochondrial respiratory chain. This study examined the impact of ferric nitrilacetic acid (Fe-NTA)-mediated iron overload on mitochondrial damage and ROS production in HCV core protein-expressing HepG2more » (human HCC) cells (Hep39b cells). A decrease in mitochondrial membrane potential and ROS production were observed following Fe-NTA treatment. After continuous exposure to Fe-NTA for six days, cell toxicity was observed in Hep39b cells, but not in mock (vector-transfected) HepG2 cells. Moreover, mitochondrial iron ({sup 59}Fe) uptake was increased in the livers of HCV core protein-expressing transgenic mice. This increase in mitochondrial iron uptake was inhibited by Ru360, a mitochondrial Ca{sup 2+} uniporter inhibitor. Furthermore, the Fe-NTA-induced augmentation of mitochondrial dysfunction, ROS production, and cell toxicity were also inhibited by Ru360 in Hep39b cells. Taken together, these results indicate that Ca{sup 2+} uniporter-mediated mitochondrial accumulation of iron exacerbates hepatocyte toxicity caused by the HCV core protein. - Highlights: • Iron accumulation in the livers of patients with hepatitis C virus (HCV) infection is thought to exacerbate oxidative stress. • The impact of iron overload on mitochondrial damage and ROS production in HCV core protein-expressing cells were examined. • Mitochondrial iron uptake was increased in the livers of HCV core protein-expressing transgenic mice. • Ca{sup 2+} uniporter-mediated mitochondrial accumulation of iron exacerbates hepatocyte toxicity caused by the HCV core protein.« less
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