Myocardial lipin1 protects the heart against ischemic injury by preserving lipid homeostasis
Jiaxi Guo, Kohei Karasaki, Kazutaka Ueda, Manami Katoh, Masaki Hashimoto, Toshiyuki Ko, Masato Ishizuka, Satoshi Bujo, Chunxia Zhao, Risa Kishikawa, Haruka Yanagisawa-Murakami, Hiroyuki Sowa, Bowen Zhai, Mutsuo Harada, Seitaro Nomura, Norihiko Takeda, Brian N. Finck, Haruhiro Toko, Issei Komuro
Jiaxi Guo, Kohei Karasaki, Kazutaka Ueda, Manami Katoh, Masaki Hashimoto, Toshiyuki Ko, Masato Ishizuka, Satoshi Bujo, Chunxia Zhao, Risa Kishikawa, Haruka Yanagisawa-Murakami, Hiroyuki Sowa, Bowen Zhai, Mutsuo Harada, Seitaro Nomura, Norihiko Takeda, Brian N. Finck, Haruhiro Toko, Issei Komuro
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Research Article Cardiology Metabolism

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

Abstract

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.

Authors

Jiaxi Guo, Kohei Karasaki, Kazutaka Ueda, Manami Katoh, Masaki Hashimoto, Toshiyuki Ko, Masato Ishizuka, Satoshi Bujo, Chunxia Zhao, Risa Kishikawa, Haruka Yanagisawa-Murakami, Hiroyuki Sowa, Bowen Zhai, Mutsuo Harada, Seitaro Nomura, Norihiko Takeda, Brian N. Finck, Haruhiro Toko, Issei Komuro

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Figure 4

Accumulation of lipid droplets in infarcted hearts.

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Accumulation of lipid droplets in infarcted hearts. (A) One week after M...
(A) One week after MI, hearts were Bodipy-stained to calculate lipid droplet numbers using ImageJ. LDs were stained by Bodipy in green, the nucleus was stained by DAPI in blue, and membranes were stained by WGA in red. While no disparities were noted in the sham group, cKO mice displayed fewer lipid droplets in the remote zone compared with control mice, whereas cOE mice exhibited more lipid droplets in the border and remote zones. n = 3 each. Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01 by ordinary 1-way ANOVA. Scale bars: 10 μm. (B) The content in infarct hearts of TAG was observed, which showed that the storage of TAG was reduced after MI in cKO mice compared with their littermate controls. On the contrary, there is an increased tendency of TAG in cOE mice than the controls. n = 12 [Ctl(cKO)], n = 4 (cKO), n = 5 [Ctl(cOE)], n = 4 (cOE). Data are presented as the mean ± SEM. *P < 0.05 by unpaired 2-tailed t test. (C) Reduced FFA storage was observed in cKO mice. Conversely, cOE mice exhibited increased FFA expression after MI. n = 9 [Ctl(cKO)], n = 4 (cKO), n = 7 [Ctl(cOE)], n = 3 (cOE). Data are presented as the mean ± SEM. ****P < 0.0001 by unpaired 2-tailed t test.