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PERM1 regulates genes involved in fatty acid metabolism in the heart by interacting with PPARα and PGC-1α.

ABSTRACT: PERM1 (PGC-1/ERR-induced regulator in muscle 1) is a muscle-specific protein induced by PGC-1 and ERRs. Previous studies have shown that PERM1 promotes mitochondrial biogenesis and metabolism in cardiomyocytes in vitro. However, the role of endogenous PERM1 in the heart remains to be investigated with loss-of-function studies in vivo. We report the generation and characterization of systemic Perm1 knockout (KO) mice. The baseline cardiac phenotype of the homozygous Perm1 KO mice appeared normal. However, RNA-sequencing and unbiased pathway analyses showed that homozygous downregulation of PERM1 leads to downregulation of genes involved in fatty acid and carbohydrate metabolism in the heart. Transcription factor binding site analyses suggested that PPARα and PGC-1α are involved in changes in the gene expression profile. Chromatin immunoprecipitation assays showed that PERM1 interacts with the proximal regions of PPAR response elements (PPREs) in endogenous promoters of genes involved in fatty acid oxidation. Co-immunoprecipitation and reporter gene assays showed that PERM1 promoted transcription via the PPRE, partly in a PPARα and PGC-1α dependent manner. These results suggest that endogenous PERM1 is involved in the transcription of genes involved in fatty acid oxidation through physical interaction with PPARα and PGC-1α in the heart in vivo.

SUBMITTER: Huang CY

PROVIDER: S-EPMC9418182 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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PERM1 regulates genes involved in fatty acid metabolism in the heart by interacting with PPARα and PGC-1α.

Huang Chun-Yang CY Oka Shin-Ichi SI Xu Xiaoyong X Chen Chian-Feng CF Tung Chien-Yi CY Chang Ya-Yuan YY Mourad Youssef Y Vehra Omair O Ivessa Andreas A Yehia Ghassan G Romanienko Peter P Hsu Chiao-Po CP Sadoshima Junichi J

Scientific reports 20220826 1

PERM1 (PGC-1/ERR-induced regulator in muscle 1) is a muscle-specific protein induced by PGC-1 and ERRs. Previous studies have shown that PERM1 promotes mitochondrial biogenesis and metabolism in cardiomyocytes in vitro. However, the role of endogenous PERM1 in the heart remains to be investigated with loss-of-function studies in vivo. We report the generation and characterization of systemic Perm1 knockout (KO) mice. The baseline cardiac phenotype of the homozygous Perm1 KO mice appeared normal. ...[more]

PMID: 36028747

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Project description:AimsPERM1 is a striated muscle-specific regulator of mitochondrial bioenergetics. We previously demonstrated that PERM1 is downregulated in the failing heart and that PERM1 positively regulates metabolic genes known as targets of the transcription factor ERRα and its coactivator PGC-1α in cultured cardiomyocytes. The aims of this study were to determine the effect of loss of PERM1 on cardiac function and energetics using newly generated Perm1-knockout (Perm1 -/-) mice and to investigate the molecular mechanisms of its transcriptional control.Methods and resultsEchocardiography showed that ejection fraction and fractional shortening were lower in Perm1 -/- mice than in wild-type mice (both p < 0.05), and the phosphocreatine-to-ATP ratio was decreased in Perm1 -/- hearts (p < 0.05), indicating reduced contractile function and energy reserves of the heart. Integrated proteomic and metabolomic analyses revealed downregulation of oxidative phosphorylation and upregulation of glycolysis and polyol pathways in Perm1 -/- hearts. To examine whether PERM1 regulates energy metabolism through ERRα, we performed co-immunoprecipitation assays, which showed that PERM1 bound to ERRα in cardiomyocytes and the mouse heart. DNA binding and reporter gene assays showed that PERM1 was localized to and activated the ERR target promoters partially through ERRα. Mass spectrometry-based screening in cardiomyocytes identified BAG6 and KANK2 as potential PERM1's binding partners in transcriptional regulation. Mammalian one-hybrid assay, in which PERM1 was fused to Gal4 DNA binding domain, showed that the recruitment of PERM1 to a gene promoter was sufficient to activate transcription, which was blunted by silencing of either PGC-1α, BAG6, or KANK2.ConclusionThis study demonstrates that PERM1 is an essential regulator of cardiac energetics and function and that PERM1 is a novel transcriptional coactivator in the ERRα/PGC-1α axis that functionally interacts with BAG6 and KANK2.

Project description:To investigate the functions of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the goose fatty liver, a total of 30 healthy 63-day-old male Landes geese were selected and randomly assigned to control group and overfeeding group. The overexpression or RNA interference assay of PGC-1α was performed in goose primary hepatocytes. Our data showed that the PGC-1α expression was increased in fatty liver. The abundance of mitochondrial biosynthesis-related and energy metabolism-related genes, including mitochondrial transcription factor A (TFAM), mitochondrial transcription factor B1 (TFB1M), mitochondrial transcription factor B2 (TFB2M), nuclear respiratory factor 1 (NRF1), DNA topoisomerase I mitochondrial (TOP1MT), peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC-1β), sirtuin 3 (SIRT3), mitochondrially encoded cytochrome B (CYTB), and AMP-activated protein kinase alpha (AMPKα) were significantly increased in fatty liver. The abundance of TFAM, TFB1M, TFB2M, NRF1, and TOP1MT transcript was induced by PGC-1α overexpression, but inhibited by PGC-1α interference in primary hepatocytes. The mRNA expression levels of PGC-1β, SIRT3, SIRT5, CYTB, and AMPKα were significantly enhanced after PGC-1α overexpression. However, the mRNA expression levels of PGC-1β, SIRT5 and AMPKα were decreased after PGC-1α interference. Furthermore, we observed a significant increase in the mitochondrial DNA (mtDNA) copy number, the activity of mitochondrial respiratory chain complex Ⅳ (MRCC Ⅳ), succinate dehydrogenase (SDH), malate dehydrogenase (MDH), and the NAD+/NADH ratio in fatty liver. But the activity of MRCC Ⅴ, as well as the levels of ADP and ATP in fatty liver were reduced. Additionally, the mtDNA copy number, the activity of MRCC Ⅰ, MRCC Ⅲ-Ⅴ, SDH, and MDH, and NAD+/NADH ratio were enhanced by PGC-1α overexpression; Whereas the mtDNA copy number, the activity of MRCC Ⅰ, SDH, and MDH, and the ratio of NAD+/NADH were inhibited by PGC-1α interference. In conclusion, these findings suggest that PGC-1α improves mitochondrial biosynthesis and energy metabolism in goose fatty liver, which may be an adaptive mechanism for goose fatty liver to cope with steatosis.

Project description:ObjectiveThe aim of this study was to eluc\idate the preventive and therapeutic effects and the underlying mechanisms of Huoxue Huatan Decoction (HXHT) on myocardial ischemia/reperfusion (I/R) injury in hyperlipidemic rats.MethodsAn I/R model was established in hyperlipidemic Wistar rats. After 4-8 weeks of HXHT treatment, the physical signs of rats were observed. Lipid metabolism, myocardial enzyme spectrum, cardiac function, myocardial histomorphology, and mitochondrial biosynthesis were investigated by a biochemical method, ultrasonography, electron microscopy, pathological examination, real-time PCR, and Western blot.ResultsHXHT can affect lipid metabolism at different time points and significantly reduce the levels of cholesterol (CHO), triglyceride (TG), high-density lipid-cholesterol (HDL-C), and low-density lipid-cholesterol (LDL-C) in hyperlipidemic rats (P < 0.05 or P < 0.01); it can significantly reduce the levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), reduce the myocardial infarct size and myocardial ischemic area, and improve cardiac function. The results of myocardial histomorphology showed that HXHT could protect myocardial cells, relieve swelling, reduce the number of cardiac lipid droplets, and improve myocardial mitochondrial function. HXHT could significantly increase the levels of total superoxide dismutase (T-SOD) and succinate dehydrogenase (SDH) (P < 0.05 or P < 0.01), increase CuZn-superoxide dismutase (CuZn-SOD) and glutathione-peroxidase (GSH-Px) levels, and decrease the levels of malondialdehyde (MDA) (P < 0.05); it could increase the mRNA and protein expression levels of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α), peroxisome proliferator-activated receptor alpha (PPARα), nuclear respiratory factor 1 (NRF1), and mitochondrial transcription factor A (mtTFA) (P < 0.05 or P < 0.01), and increase the synthesis of mitochondrial DNA (mtDNA) (P < 0.01).ConclusionHXHT can reduce myocardial I/R injury in hyperlipidemic rats. The protective mechanisms may involve a reduction in blood lipids, enhancement of PGC-1α-PPARα pathway activity, and, subsequently, an increase in fatty acid β-oxidation, which may provide the required input for mitochondrial energy metabolism. HXHT can additionally enhance PGC-1α-NRF1-mtTFA pathway activity and, subsequently, increase the antioxidant capacity, promote mtDNA synthesis, and reduce mitochondrial damage. The two pathways use PGC-1α as the intersection point to protect mitochondrial structure and function, reduce I/R-induced injury, and improve cardiac function.

Dataset Information

PERM1 regulates genes involved in fatty acid metabolism in the heart by interacting with PPARα and PGC-1α.

Publications

PERM1 regulates genes involved in fatty acid metabolism in the heart by interacting with PPARα and PGC-1α.

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