Lipotoxicity contributes to endothelial dysfunction: A focus on the contribution from ceramide

Abstract

Cardiovascular complications are the leading causes of morbidity and mortality in individuals with obesity, type 2 diabetes mellitus (T2DM), and insulin resistance. Complications include pathologies specific to large (atherosclerosis, cardiomyopathy) and small (retinopathy, nephropathy, neuropathy) vessels. Common among all of these pathologies is an altered endothelial cell phenotype i.e., endothelial dysfunction. A crucial aspect of endothelial dysfunction is reduced nitric oxide (NO) bioavailability. Hyperglycemia, oxidative stress, activation of the renin-angiotensin system, and increased pro-inflammatory cytokines are systemic disturbances in individuals with obesity, T2DM, and insulin resistance and each of these contribute independently and synergistically to decreasing NO bioavailability. This review will examine the contribution from elevated circulating fatty acids in these subjects that lead to lipotoxicity. Particular focus will be placed on the fatty acid metabolite ceramide.

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…Fat deposits in such ectopic tissues are unhealthy and can initiate tissue inflammation, endoplasmic reticulum (ER) stress, and endothelial dysfunction, accelerating the development of obesityassociated pathologies, such as insulin resistance and type 2 diabetes (T2D) (Hotamisligil et al, 1993(Hotamisligil et al, , 1996Ozcan et al, 2004). In line with this proposed model of lipotoxicity, ectopic accumulation of reactive lipid species such as diacylglycerol, free fatty acids, free cholesterol, and ceramides have all been demonstrated to impair systems metabolism through local tissue inflammation and induction of ER stress (Unger, 2002;Virtue and Vidal-Puig, 2008;Symons and Abel, 2013;Contreras et al, 2014).…”

Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54–96 years from the Baltimore Longitudinal Study of Aging

“…Treatments targeting ceramides may be potentially very effective for preventing or treating these conditions (Mielke et al ., 2015). For example, elevated plasma ceramides cause vascular endothelial dysfunction by promoting endothelial cell growth arrest, oxidative stress, senescence and death, disrupting insulin signaling and increasing inflammation (Zhang et al ., 2012; Symons & Abel, 2013). Perhaps through these same mechanisms, ceramides may contribute to the early stages of atherosclerosis (Ichi et al ., 2006; Bismuth et al ., 2008) and the accumulation of ceramide in the myocardium may cause cardiac dysfunction in obese and diabetic individuals, even in the absence of hypertension and myocardial ischemia (Park & Goldberg, 2012).…”

The Mechanisms of Heart Failure Development in Obesity

“…Эффекты адипонек-тина опосредуются через их потенцирование дей-ствий инсулина, повышения образования NO, стиму-лирование синтеза простагландинов через ЦОГ-2, и активацию аденозинмонофосфата, который также активирует протеинкиназу и подавляет α-адрено-рецептор-стимулированную гипертрофию КМЦ [26]. Адипонектин регулирует тканевой уровень церами-дов путем активации церамидазы, которая гидроли-зует церамид [27].…”

“…Лептин сти-мулирует сердечную гипертрофию напрямую через сложные механизмы сигнализирования клеток и кос-венно через свое влияние на артериальное давление и СНС [26]. Лептин также оказывает отрицательное инотропное воздействие на кардиомиоциты через эндогенную продукцию NO.…”