Cysteine-rich 61 inhibition attenuates hepatic insulin resistance and improves lipid metabolism in high-fat diet fed mice and HepG2 cells.

Autor: Heo YJ; Institute of Medical Science, Ajou University School of Medicine, Suwon, Republic of Korea., Park J; Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea., Lee N; Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea., Choi SE; Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea., Jeon JY; Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea., Han SJ; Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea., Kim DJ; Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea., Lee KW; Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea., Kim HJ; Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Aug 15; Vol. 38 (15), pp. e23859.
DOI: 10.1096/fj.202400860R
Abstrakt: Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with insulin resistance development. Hepatic lipid accumulation and inflammation are considered the main drivers of hepatic insulin resistance in MASLD. Cysteine-rich 61 (Cyr61 also called CCN1), a novel secretory matricellular protein, is implicated in liver inflammation, and its role in MASLD is not clearly understood. Therefore, we investigated the role of Cyr61 in hepatic insulin resistance and lipid metabolism as major factors in MASLD pathogenesis. In high-fat diet (HFD)-fed C57BL/6J mice, Cyr61 was downregulated or upregulated via viral transduction. Measurements of glucose homeostasis, histological assessment of liver tissues, and gene expression and signaling pathways of lipogenesis, fatty acid oxidation, and inflammation were performed using liver samples from these mice. Cyr61 levels in HepG2 cells were reduced using RNAi-mediated gene knockdown. Inflammation and insulin resistance were evaluated using real-time polymerase chain reaction and western blotting. HFD/AAV-shCyr61 mice exhibited enhanced glucose tolerance via the protein kinase B pathway, reduced hepatic inflammation, decreased lipogenesis, and increased fatty acid oxidation. Notably, HFD/AAV-shCyr61 mice showed elevated protein expression of sirtuin 6 and phosphorylated-AMP-activated protein kinase. In vitro experiments demonstrated that inhibition of Cyr61 downregulated pro-inflammatory cytokines such as interleukin-1 beta, IL-6, and tumor necrosis factor-alpha via the nuclear factor kappa B/c-Jun N-terminal kinase pathway, and alleviated insulin resistance. Cyr61 affected hepatic inflammation, lipid metabolism, and insulin resistance. Inhibition of Cyr61 reduced inflammation, recovered insulin resistance, and altered lipid metabolism in vivo and in vitro. Therefore, Cyr61 is a potential therapeutic target in MASLD.
(© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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