Abstract
ObjectivesThe endoplasmic reticulum (ER) chaperone tauroursodeoxycholic acid (TUDCA) has exhibited promises in the treatment of obesity, although its impact on obesity-induced cardiac dysfunction is unknown. This study examined the effect of TUDCA on cardiomyocyte function in high-fat diet-induced obesity.MethodsAdult mice were fed low or high fat diet for 5 months prior to treatment of TUDCA (300 mg/kg. i.p., for 15d). Intraperitoneal glucose tolerance test (IPGTT), cardiomyocyte mechanical and intracellular Ca2+ property, insulin signaling molecules including IRS-1, Akt, AMPK, ACC, GSK-3β, c-Jun, ERK and c-Jun N terminal kinase (JNK) as well as ER stress and intracellular Ca2+ regulatory proteins were examined. Myocardial ultrastructure was evaluated using transmission electron microscopy (TEM).ResultsHigh-fat diet depressed peak shortening (PS) and maximal velocity of shortening/relengthenin as well as prolonged relengthening duration. TUDCA reversed or overtly ameliorated high fat diet-induced cardiomyocyte dysfunction including prolongation in relengthening. TUDCA alleviated high-fat diet-induced decrease in SERCA2a and phosphorylation of phospholamban, increase in ER stress (GRP78/BiP, CHOP, phosphorylation of PERK, IRE1α and eIF2α), ultrastructural changes and mitochondrial permeation pore opening. High-fat diet feeding inhibited phosphorylation of AMPK and promoted phosphorylation of GSK-3β. TUDCA prevented high fat-induced dephosphorylation of AMPK but not GSK-3β. High fat diet promoted phosphorylation of IRS-1 (Ser307), JNK, and ERK without affecting c-Jun phosphorylation, the effect of which with the exception of ERK phosphorylation was attenuated by TUDCA.ConclusionsThese data depict that TUDCA may ameliorate high fat diet feeding-induced cardiomyocyte contractile and intracellular Ca2+ defects through mechanisms associated with mitochondrial integrity, AMPK, JNK and IRS-1 serine phosphorylation.
Highlights
According to the 2011 estimate of the Center for Disease Control and Prevention (CDC), nearly 26 million Americans are afflicted with diabetes mellitus while 79 million individuals are considered prediabetic[1]
Among the array of pathophysiological machineries identified for obesity pathology such as genetics, inflammation, insulin resistance, oxidative stress, autophagy and apoptosis, enhanced endoplasmic reticulum (ER) stress has emerged as a crucial factor in obesityinduced metabolic derangement [5]
General feature of mice and Intraperitoneal glucose tolerance test (IPGTT) As expected, high fat diet significantly increased body weight, the effect of which was unaffected by tauroursodeoxycholic acid (TUDCA) treatment (LF: 27.960.6 g; HF: 33.061.1 g; LF-TUDCA: 27.660.9 g; HFTUDCA: 33.761.5 g; p,0.05 between any LF and HF groups, n = 5–7 mice per group)
Summary
According to the 2011 estimate of the Center for Disease Control and Prevention (CDC), nearly 26 million Americans are afflicted with diabetes mellitus while 79 million individuals are considered prediabetic[1]. Both clinical and experimental evidence has identified a variety of predisposing factors for diabetes, with obesity being one independent causative factor for the increased prevalence of type 2 diabetes [2]. Ample evidence has depicted a pivotal role of ER stress in the pathogenesis of insulin resistance, alcoholism, diabetes and obesity [5,7,8,9]. AMPK has been demonstrated to retard ER stress through eEF2 inactivation, resulting in preservation of sarco(endo)plasmic reticulum (SERCA) function and intracellular Ca2+ homeostasis [17,18]
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