Manifestations and mechanisms of myocardial lipotoxicity in obesity

Abstract

Environmental and socioeconomic changes over the past thirty years have contributed to a dramatic rise in the worldwide prevalence of obesity. Heart disease is amongst the most serious health risks of obesity, with increases in both atherosclerotic coronary heart disease and heart failure among obese individuals. In this review, we focus on primary myocardial alterations in obesity that include hypertrophic remodelling and diastolic dysfunction. Obesityassociated perturbations in myocardial and systemic lipid metabolism are important contributors to cardiovascular complications of obesity. Accumulation of excess lipid in nonadipose cells of the cardiovascular system can cause cell dysfunction and cell death, a process known as lipotoxicity. Lipotoxicity has been modelled in mice using high-fat diet feeding, inbred lines with mutations in leptin receptor signalling, and in genetically engineered mice with enhanced myocardial fatty acid uptake, altered lipid droplet homoeostasis or decreased cardiac fatty acid oxidation. These studies, along with findings in cell culture model systems, indicate that the molecular pathophysiology of lipid overload involves endoplasmic reticulum stress, alterations in autophagy, de novo ceramide synthesis, oxidative stress, inflammation and changes in gene expression. We highlight recent advances that extend our understanding of the impact of obesity and altered lipid metabolism on cardiac function.

CTRP9 knockout exaggerates lipotoxicity in cardiac myocytes and high‐fat diet‐induced cardiac hypertrophy through inhibiting the LKB1/AMPK pathway

“…In addition, emerging evidence also shows ER stress has a major role in the progression of cardiac lipotoxicity . For in vitro studies, palmitate treatment in NRCMs decreased cell viability and induced ER stress‐mediated apoptosis, which was attenuated by exogenous CTRP9 in a dose‐dependent manner.…”

“…In addition, emerging evidence also shows ER stress has a major role in the progression of cardiac lipotoxicity. 8,9 For in vitro studies, palmitate treatment in NRCMs decreased cell viability and induced ER stress-mediated apoptosis, which was attenuated by exogenous CTRP9 in a dose-dependent manner. Furthermore, we demonstrated that CTRP9 deficiency exacerbated HFD-induced ER stress-related F I G U R E 7 AMPK phosphorylation is weakened in HFD-fed CTRP9 knockout mice and palmitate-treated NRCMs.…”

“…Unoxidized FAs in cardiac myocytes could produce oxidative stress and ER stress, resulting in lipotoxicty . Oxidative stress and ER stress‐initiated apoptotic signalling pathway play crucial roles in the pathogenesis of obesity‐induced cardiac abnormality …”

“…5,6 Oxidative stress and ER stress-initiated apoptotic signalling pathway play crucial roles in the pathogenesis of obesity-induced cardiac abnormality. [7][8][9] AMP-activated protein kinase (AMPK) is a major cellular sensor of energy balance in mammalian cells. 10 Liver kinase B1 (LKB1) can act as major upstream kinases of AMPK and phosphorylate AMPK at Thr172.…”

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

“…These findings suggest that the duration of fasting may be a stress, and will need to be carefully titrated depending upon the species (as 24 hours of fasting in a mouse is perhaps equivalent to a much longer period of fast in humans given differences in lifespan). Obesity and diabetes induce a plethora of myocardial changes that culminate in a clinically observed entity of diabetic cardiomyopathy (93) which is characterized by myocardial lipid overload (200). Whether these beneficial effects of intermittent fasting are also observed in the diabetic myocardium and are the subject of active investigation.…”