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Long term N-acetylcysteine administration rescues liver steatosis via endoplasmic reticulum stress with unfolded protein response in mice.

ABSTRACT: BACKGROUND:Fat accumulation in the liver contributes to the development of non-alcoholic fatty liver disease (NAFLD). N-acetylcysteine (NAC) is an antioxidant, acting both directly and indirectly via upregulation of cellular antioxidants. We examined the mechanisms of liver steatosis after 12?months high fat (HF) diet and tested the ability of NAC to rescue liver steatosis. METHODS:Seven-week-old C57BL/6 (B6) male mice were administered HF diet for 12?months (HF group). Two other groups received HF diet for 12?months accompanied by NAC for 12?months (HFD?+?NAC(1-12)) or 6?months (HFD?+?NAC(1-6)). The control group was fed regular diet for 12?months (CD group). RESULTS:Liver steatosis was more pronounced in the HF group than in the CD group after 12?month feeding. NAC intake for 6 or 12?months decreased liver steatosis in comparison with HF diet (p?

SUBMITTER: Tsai CC

PROVIDER: S-EPMC7249367 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Long term N-acetylcysteine administration rescues liver steatosis via endoplasmic reticulum stress with unfolded protein response in mice.

Tsai Ching-Chou CC Chen Yu-Jen YJ Yu Hong-Ren HR Huang Li-Tung LT Tain You-Lin YL Lin I-Chun IC Sheen Jiunn-Ming JM Wang Pei-Wen PW Tiao Mao-Meng MM

Lipids in health and disease 20200525 1

<h4>Background</h4>Fat accumulation in the liver contributes to the development of non-alcoholic fatty liver disease (NAFLD). N-acetylcysteine (NAC) is an antioxidant, acting both directly and indirectly via upregulation of cellular antioxidants. We examined the mechanisms of liver steatosis after 12 months high fat (HF) diet and tested the ability of NAC to rescue liver steatosis.<h4>Methods</h4>Seven-week-old C57BL/6 (B6) male mice were administered HF diet for 12 months (HF group). Two other ...[more]

PMID: 32450865

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Project description:Cellular stress-mediated chaperones are linked to liver macrophage activation and inflammation in alcohol-associated liver disease (ALD). In this study, we investigate the role of endoplasmic reticulum (ER) resident stress chaperone GP96/HSP90B1/GRP94, paralog of the HSP90 family, in ALD pathogenesis. We hypothesize that ER resident chaperone, heat shock protein GP96, plays a crucial role in alcohol-associated liver inflammation and contributes to liver injury. We show high expression of GP96/HSP90B1 and GRP78/HSPA5 in human alcohol-associated hepatitis livers as well as in mouse ALD livers with induction of GP96 prominent in alcohol-exposed macrophages. Myeloid-specific GP96 deficient (M-GP96KO) mice failed to induce alcohol-associated liver injury. Alcohol-fed M-GP96KO mice exhibit significant reduction in steatosis, serum endotoxin, and pro-inflammatory cytokines compared with wild-type mice. Anti-inflammatory cytokines interleukin-10 and transforming growth factor β, as well as activating transcription factor 3 and triggering receptor expressed on myeloid cells 2, markers of restorative macrophages, were higher in alcohol-fed M-GP96KO livers. M-GP96KO mice exhibit protection in a model of endotoxin-mediated liver injury in vivo, which is in agreement with reduced inflammatory responses during ex vivo lipopolysaccharide/endotoxin- stimulated bone marrow-derived macrophages from M-GP96KO mice. Furthermore, we show that liver macrophages from alcohol-fed M-GP96KO mice show compensatory induction of GRP78 messenger RNA, likely due to increased splicing of X-box binding protein-1. Finally, we show that inhibition of GP96 using a specific pharmacological agent, PU-WS13 or small interfering RNA, alleviates inflammatory responses in primary macrophages. Conclusion: Myeloid ER resident GP96 promotes alcohol-induced liver damage through activation of liver macrophage inflammatory responses, alteration in lipid homeostasis, and ER stress. These findings highlight a critical role for liver macrophage ER resident chaperone GP96/HSP90B1 in ALD, and its targeted inhibition represents a promising therapeutic approach in ALD.

Dataset Information

Long term N-acetylcysteine administration rescues liver steatosis via endoplasmic reticulum stress with unfolded protein response in mice.

Publications

Long term N-acetylcysteine administration rescues liver steatosis via endoplasmic reticulum stress with unfolded protein response in mice.

Similar Datasets

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