Selective autophagy associated with iron overload aggravates non-alcoholic steatohepatitis via ferroptosis.

Autor:	Honma K; Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama 700-8558, Japan., Kirihara S; Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama 700-8558, Japan., Nakayama H; Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama 700-8558, Japan., Fukuoka T; Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama 700-8558, Japan., Ohara T; Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama University, Okayama 700-8558, Japan., Kitamori K; College of Human Life and Environment, Kinjo Gakuin University, Nagoya 463-8521, Japan., Sato I; Academic Field of Health Science, Okayama University, Okayama 700-8558, Japan., Hirohata S; Academic Field of Health Science, Okayama University, Okayama 700-8558, Japan., Fujii M; Department of Medical Technology, Ehime Prefectural University of Health Sciences, Ehime 791-2101, Japan., Yamamoto S; Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama 700-8558, Japan.; Academic Field of Health Science, Okayama University, Okayama 700-8558, Japan., Ran S; HeiLongjiang Provincial Center for disease control and prevention, Harbin 150030, China., Watanabe S; Academic Field of Health Science, Okayama University, Okayama 700-8558, Japan.
Jazyk:	angličtina
Zdroj:	Experimental biology and medicine (Maywood, N.J.) [Exp Biol Med (Maywood)] 2023 Jul; Vol. 248 (13), pp. 1112-1123. Date of Electronic Publication: 2023 Aug 30.
DOI:	10.1177/15353702231191197
Abstrakt:	Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that causes cirrhosis and hepatocellular carcinoma. Iron is an essential trace element in the body; however, excess iron can cause tissue damage and dysfunction. Iron overload is often observed in patients with NASH, and the amount of iron accumulated in the liver positively correlates with the histological severity of NASH. Ferroptosis, a novel form of iron-dependent cell death, is caused by the accumulation of lipid peroxidation and oxidative stress and is related to NASH. In addition, ferroptosis is closely related to autophagy, an intracellular self-degradation process. Although autophagy has many beneficial effects, it may also be harmful to the organism, for example, inducing ferroptosis. It is unclear whether iron overload aggravates NASH via autophagy. The aim of this research is to determine the mechanism by which iron overload induces ferroptosis via autophagy and aggravates NASH. Stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr) were divided into two groups and fed a high-fat and high-cholesterol (HFC) diet for eight weeks. Iron dextran was administered to the Fe group in addition to the HFC diet. Blood analysis, histological staining, calcineurin activity assay, quantitative reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence staining, and electron microscopy were performed. The results showed that iron overload promoted autophagy via nuclear translocation of transcription factor EB (TFEB) and induced ferritinophagy, which is the autophagic degradation of ferritin. In addition, the HFC diet induced lipophagy, the autophagic degradation of lipid droplets. The Fe group also exhibited promoted ferroptosis and aggravated hepatic inflammation and fibrosis. In conclusion, iron overload accelerates ferritinophagy and lipophagy, aggravating NASH pathology via ferroptosis. These findings indicate the therapeutic potential of inhibiting autophagy and ferroptosis for treating NASH. Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Databáze:	MEDLINE
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