Chronic ethanol consumption increases cardiomyocyte fatty acid uptake and decreases ventricular contractile function in C57BL/6J mice

Abstract

Alcohol, a major cause of human cardiomyopathy, decreases cardiac contractility in both animals and man. However, key features of alcohol-related human heart disease are not consistently reproduced in animal models. Accordingly, we studied cardiac histology, contractile function, cardiomyocyte long chain fatty acid (LCFA) uptake, and gene expression in male C57BL/6J mice consuming 0, 10, 14, or 18% ethanol in drinking water for 3 months. At sacrifice, all EtOH groups had mildly decreased body and increased heart weights, dose-dependent increases in cardiac triglycerides and a marked increase in cardiac fatty acid ethyl esters. [3H]-oleic acid uptake kinetics demonstrated increased facilitated cardiomyocyte LCFA uptake, associated with increased expression of genes encoding the LCFA transporters CD36 and Slc27a1 (FATP1) in EtOH-fed animals. Although SCD-1 expression was increased, lipidomic analysis did not indicate significantly increased de novo LCFA synthesis. By echocardiography, ejection fraction (EF) and the related fractional shortening (FS) of left ventricular diameter during systole were reduced and negatively correlated with cardiac triglycerides. Expression of myocardial PGC-1α and multiple downstream target genes in the oxidative phosphorylation pathway, including several in the electron transport and ATP synthase complexes of the inner mitochondrial membrane, were down-regulated. Cardiac ATP was correspondingly reduced. The data suggest that decreased expression of PGC-1α and its target genes result in decreased cardiac ATP levels, which may explain the decrease in myocardial contractile function caused by chronic EtOH intake. This model recapitulates important features of human alcoholic cardiomyopathy and illustrates a potentially important pathophysiologic link between cardiac lipid metabolism and function.

Expression Profiling of Circular RNAs and Micrornas in Heart Tissue of Mice with Alcoholic Cardiomyopathy

“…In the present study, myocardial changes were found in the chronic alcohol-fed mice, such as fatty acid accumulation, cardiomyocyte vacuolization, myocardial myofibril loss and disarray, sarcoplasmic reticulum edema, and swollen disrupted mitochondria, which are consistent with those of previous reports [31-33]. The mechanisms underlying ACM include oxidative stress [4, 5], impaired mitochondrial bioenergetics [2], and derangements in fatty acid metabolism and transport [6]. Our observations in the alcohol-treated mice using light and electron microscopy are in line with those seen in postmortem myocardial biopsies from human subjects with ACM [22, 34], even though we have no evidence that our mice developed dilated cardiomyopathy (DCM).…”

“…Chronic alcohol consumption leads to a number of alterations in the metabolic function of the heart [2, 23] and results in a deterioration of heart function [6, 24-26], which is a leading cause of cardiomyopathy. The exact amount and duration of alcohol consumption associated with the development of ACM is humans are variable.…”

“…This devastating disease is one of the most prevalent causes of non-ischemic sudden cardiac death [1]. Although some studies have suggested the pathogenesis of ACM, including mitochondrial damage [2], cardiotoxicity of alcohol, oxidative stress [3-5], and the accumulation of fatty acid ethyl esters [6], the real pathological factors remain unknown. Genetic regulation plays an important role in the occurrence of ACM.…”

Alcoholic Cardiomyopathy: Basic Aspects of Epidemiology, Pathogenesis and Pharmacotherapy

“…При ЭХОКГ было выявлено снижение фракции выброса левого желу-дочка (ЛЖ), которое отрицательно коррелировало с уровнем триглицеридов. Снижение экспрессии коак-тиватора гамма-рецепторов, активируемых проли-фераторами пероксисом (PGC-1α) и его таргетных ге-нов, привело к снижению уровня сердечной АТФ, что, в свою очередь, вызывает нарушение сократи-тельной функции миокарда, вызванной хроническим употреблением алкоголя [34].…”

“…Подобно другим дилатационным КМП, алкогольная характеризуется дилатацией (рас-ширением) ЛЖ, истончением стенок миокарда, нару-шением его сократительной функции, при этом отсут-ствуют заболевания коронарных артерий либо дефи-цит питательных веществ [34,35].…”