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IntroductionMetabolic syndrome (MetS) is considered as a complex, intertwined multiple risk factors that directly increase the risk of various metabolic diseases, especially cardiovascular atherosclerotic diseases and diabetes mellitus type 2. While lifestyle changes, including dietary intervention are effective in mitigating or preventing MetS, there are no specific therapies against MetS. Typical western diets comprise of high saturated fatty acid, cholesterol, and simple sugar; consequently their consumption may increase the potential pathological developmental risk of MetS. Partial replacement of dietary fatty acids with polyunsaturated fatty acids (PUFAs) is widely recommended measure to manage MetS-related disorders.MethodsIn the present study, we used rat model to investigate the role of n-3 PUFA enriched beef tallows (BT) on MetS and tunicamycin (TM)-induced endoplasmic reticulum (ER) stress, by partially replacing dietary fat (lard) with equal amounts of two different BTs; regular BT or n-3 PUFA-enriched BT. The experimental rats were randomly assigned to three different dietary groups (n = 16 per group): (1) high-fat and high-cholesterol diet (HFCD); (2) HFCD partially replaced with regular BT (HFCD + BT1); (3) HFCD partially replaced with n-3 enhanced BT (w/w) (HFCD + BT2). After 10 weeks of dietary intervention, each experimental rodent was intraperitoneally injected with either phosphate-buffered saline or 1 mg/kg body weight of TM.ResultsHFCD + BT2 showed improved dyslipidemia before TM injection, and increased serum high-density lipoprotein cholesterol (HDL-C) levels after TM injection. BT replacement groups had significantly reduced hepatic triglyceride (TG) levels, and decreased total cholesterol (TC) and TG levels in epididymal adipose tissue (EAT). Furthermore, BT replacement remarkably attenuated TM-induced unfolded protein responses (UPRs) in liver, showing reduced ER stress, with BT2 being more effective in the EAT.DiscussionTherefore, our findings suggest that partially replacing dietary fats with n-3 PUFA to lower the ratio of n-6/n-3 PUFAs is beneficial in preventing pathological features of MetS by alleviating HFCD- and/or TM-induced dyslipidemia and ER stress.

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.