Hepatitis C virus protein and iron overload induce hepatic steatosis through the unfolded protein response in mice.
OBJECTIVE
Hepatic iron overload and steatosis play critical roles in the progression of hepatitis C virus (HCV)-associated chronic liver disease. However, how these two pathophysiological features affect each other remains unknown. The aim of this study was to investigate how hepatic iron overload contributes to the development of hepatic steatosis in the presence of HCV proteins.


METHODS
Male C57BL/6 transgenic mice expressing the HCV polyprotein and nontransgenic littermates were fed an excess-iron diet or a control diet. Mice in each group were assessed for the molecules responsible for fat accumulation in the liver.


RESULTS
Hepatic iron levels were positively correlated with triglyceride concentrations in the liver for all mice. As compared with the livers of nontransgenic mice fed the control diet, the livers of transgenic mice fed the excess-iron diet showed a lower expression of carnitine palmitoyl transferase I, a higher expression of sterol-regulatory element-binding protein 1 and fatty acid synthetase and an activated unfolded protein response indicated by a higher expression of unspliced and spliced X-box DNA-binding protein 1 (XBP-1), phosphorylated eukaryotic initiation factor-2alpha (p-eIF2alpha), CCAAT/enhancer-binding protein homology protein (CHOP) and abundant autophagosomes concomitant with increased production of reactive oxygen species. Six-month treatment with the anti-oxidant N-acetyl cysteine dramatically reduced hepatic steatosis in transgenic mice fed the excess-iron diet through decreased expression of unspliced and spliced XBP-1, p-eIF2alpha, and CHOP.


CONCLUSIONS
The iron-induced unfolded protein response appears to be one of the mechanisms responsible for fat accumulation in the liver in transgenic mice expressing the HCV polyprotein.
Nishina
Sohji
S
Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Korenaga
Masaaki
M
Hidaka
Isao
I
Shinozaki
Akane
A
Sakai
Aya
A
Gondo
Toshikazu
T
Tabuchi
Mitsuaki
M
Kishi
Fumio
F
Hino
Keisuke
K
D000818:Animals; D001343:Autophagy; D002334:Carnitine O-Palmitoyltransferase / Q000032:analysis / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology*; D006526:Hepatitis C / Q000150:complications*; D019190:Iron Overload / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000032:analysis / Q000502:physiology; D014280:Triglycerides / Q000032:analysis; D056811:Unfolded Protein Response; D014764:Viral Proteins / Q000502:physiology*
D017382:Reactive Oxygen Species; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D014764:Viral Proteins; D002334:Carnitine O-Palmitoyltransferase