Myocardial lipin1 protects the heart against ischemic injury by preserving lipid homeostasis

脂质代谢 心功能曲线 二酰甘油激酶 炎症 内科学 脂滴 内分泌学 化学 药理学 心肌梗塞 心脏纤维化 纤维化 脂质信号 缺血 基因剔除小鼠 心室 脂毒性 脂肪酸 心肌保护 再灌注损伤 β氧化 医学 活性氧 促炎细胞因子 基因表达 生物化学 花生四烯酸 磷脂酸 SIRT3 新陈代谢 心室重构 下调和上调
作者
Jiaxi Guo,Kohei Karasaki,Kazutaka Ueda,Manami Katoh,Masaki Hashimoto,Toshiyuki Ko,Masato Ishizuka,Satoshi Bujo,Chunxia Zhao,Risa Kishikawa,Haruka Yanagisawa‐Murakami,Hideaki Sowa,Bowen Zhai,Mutsuo Harada,Seitaro Nomura,Norihiko Takeda,Brian N. Finck,Haruhiro Toko,Issei Komuro
出处
期刊:JCI insight [American Society for Clinical Investigation]
卷期号:10 (23)
标识
DOI:10.1172/jci.insight.183334
摘要

Impaired cardiac lipid metabolism has been reported to cause heart failure. Lipin1, a multifunctional protein, is a phosphatidate phosphatase that generates diacylglycerol from phosphatidic acid and a transcriptional cofactor that regulates lipid metabolism-related gene expression. Here, we investigated the roles of lipin1 in cardiac remodeling after myocardial infarction (MI). The expression levels of lipin1 significantly decreased in cardiomyocytes of the human failing heart and murine ischemic myocardium. Cardiomyocyte-specific Lpin1 knockout (cKO) mice showed left ventricle enlargement and reduced fractional shortening after MI, compared with control mice. This was accompanied by elevated cardiac fibrosis, accumulation of reactive oxygen species, and increased expression of inflammatory cytokines. In contrast, cardiomyocyte-specific Lpin1 overexpression (cOE) mice showed reduced fibrosis and inflammation and improved cardiac function compared with control mice. Cardiac lipid droplets (LDs) were reduced after MI in WT mouse hearts and were further downregulated in the hearts of cKO mice with a decrease in triacylglycerol and free fatty acid content, while cOE mice hearts exhibited increased LDs and lipid content. Expression levels of genes involved in fatty acid oxidation, such as Ppargc1a (PGC1A) and Acaa2, were decreased and increased in the MI hearts of cKO mice and cOE mice, respectively. These results suggest the protective role of lipin1 against ischemic injury by maintaining lipid metabolism in ischemic cardiomyocytes.
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