The role of mitofusin 2 in saturated fatty acid induced ER stress in H4IIE liver cells (1116.4)

Abstract Background Obesity-induced lipotoxicity causes cardiac dysfunction in our modern lifestyle. Previously, we have shown that an increase in cardiomyocyte membrane saturated fatty acid (SFA)/ monounsaturated FA (MUFA) ratio mediates endoplasmic reticulum (ER) stress, which was implicated in the pathogenesis of SFA-induced cardiomyopathy. Furthermore, SFA supressed Sirt1/ stearoyl-CoA desaturase-1 (SCD1, converting enzyme from SFA to MUFA) signaling, which further worsened the membrane SFA/MUFA ratio. Purpose To evaluate the effectiveness of targeting membrane fatty acid composition by MUFA. Methods and results In wild-type mice, 16-weeks SFA-rich high lard diet feeding (HLD) caused activation of PPARα signaling and the accumulation of toxic lipid intermediates (diacylglycerol and ceramide) in the heart to the same extent as a MUFA-rich high olive oil diet feeding (HOD). However, only the HLD impaired Sirt1 activity, SCD1 expression, diastolic function (increased left ventricular end-diastolic pressure (LVEDP) and end-diastolic pressure-volume relationship (EDPVR)), and cardiac remodeling (hypertrophy and fibrosis). Lipidome analysis showed that HLD-induced diastolic dysfunction coincided with an increase in membrane SFA/MUFA ratio and ER stress induction. 8-weeks HOD after 8-weeks HLD (HOD switch) showed the same degree of obesity and PPARα activation with 16-weeks HLD. By contrast, HOD switched heart were less severe Sirt1/SCD1 signaling dysregulation, increased in membrane SFA/MUFA ratio, ER stress, and cardiomyopathy (hypertrophy, fibrosis, and diastolic dysfunction) compared to 16-weeks HLD. Moreover, in cardiomyocyte-specific Sirt1 knockout mice, HOD switched heart also showed less severe increase in membrane SFA/MUFA ratio, ER stress, and cardiomyopathy compared to 16-weeks HLD although decreased SCD1 expression was not changed. Conclusions We demonstrated that MUFA-rich diet counteracted SFA-induced Sirt1/SCD1 signaling dysregulation and prevented SFA-induced increase in membrane SFA/MUFA ratio. Hence, MUFA-rich diet antagonized SFA-induced ER stress and cardiomyopathy even if Sirt1 deactivated heart (e.g., aged heart). Targeting the cardiomyocyte membrane SFA/MUFA ratio by MUFA might have a new therapeutic potential for SFA-induced cardiomyopathy. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): JSPS KAKENHI

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Abstract 357: Hepatic ERK2 Suppresses Endoplasmic Reticulum Stress, Leading to Protection from Oxidative Stress and Endothelial Dysfunction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a357 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Takehiko Kujiraoka ◽

Yasushi Satoh ◽

Makoto Ayaori ◽

Yasunaga Shiraishi ◽

Yuko Arai-Nakaya ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Fatty Acid ◽

Endothelial Dysfunction ◽

Er Stress ◽

Vascular Complications ◽

Metabolic Remodeling ◽

And Oxidative Stress

Background Insulin signaling comprises 2 major cascades, the IRS/PI3K/Akt and Ras/Raf/MEK/ERK pathways. Many studies on the tissue-specific effects of the former pathway had been conducted, however, the role of the latter cascade in tissue-specific insulin resistance had not been investigated. High glucose/fatty acid toxicity, inflammation and oxidative stress, all of which are associated with insulin resistance, can activate ERK. Liver plays a central role of metabolism and hepatosteatosis (HST) is associated with vascular diseases. The aim of this study is to elucidate the role of hepatic ERK2 in HST, metabolic remodeling and endothelial dysfunction. Methods Serum biomarkers of vascular complications in human were compared between subjects with and without HST diagnosed by echography for regular medical checkup. Next, we created liver-specific ERK2 knockout mice (LE2KO) and fed them with a high-fat/high-sucrose diet (HFHSD) for 20 weeks. The histological analysis, the expression of hepatic sarco/endoplasmic reticulum (ER) Ca 2+ -ATPase 2 (SERCA2) and glucose-tolerance/insulin-sensitivity (GT/IS) were tested. Vascular superoxide production and endothelial function were evaluated with dihydroethidium staining and isometric tension measurement of aorta. Results The presence of HST significantly increased HOMA-IR, an indicator of insulin resistance or atherosclerotic index in human. HFHSD-fed LE2KO revealed a marked exacerbation in HST and metabolic remodeling represented by the impairment of GT/IS, elevated serum free fatty acid and hyperhomocysteinemia without changes in body weight, blood pressure and serum cholesterol/triglyceride levels. In the HFHSD-fed LE2KO, mRNA and protein expressions of hepatic SERCA2 were significantly decreased, which resulted in hepatic ER stress. Induction of vascular superoxide production and remarkable endothelial dysfunction were also observed in them. Conclusions Hepatic ERK2 revealed the suppression of hepatic ER stress and HST in vivo , which resulted in protection from vascular oxidative stress and endothelial dysfunction. HST with hepatic ER stress can be a prominent risk of vascular complications by metabolic remodeling and oxidative stress in obese-related diseases.

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