The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction

Abstract

Impaired cardiac function is associated with myocardial triglyceride accumulation, but it is not clear how the lipids accumulate or whether this accumulation is detrimental. Here we show that hypoxia/ischemia-induced accumulation of lipids in HL-1 cardiomyocytes and mouse hearts is dependent on expression of the VLDL receptor (VLDLR). Hypoxia-induced VLDLR expression in HL-1 cells was dependent on HIF-1α through its interaction with a hypoxia-responsive element in the Vldlr promoter, and VLDLR promoted the endocytosis of lipoproteins. Furthermore, VLDLR expression was higher in ischemic compared with nonischemic left ventricles from human hearts and was correlated with the total lipid droplet area in the cardiomyocytes. Importantly, Vldlr -/-mice showed improved survival and decreased infarct area following an induced myocardial infarction. ER stress, which leads to apoptosis, is known to be involved in ischemic heart disease. We found that ischemia-induced ER stress and apoptosis in mouse hearts were reduced in Vldlr -/-mice and in mice treated with antibodies specific for VLDLR. These findings suggest that VLDLR-induced lipid accumulation in the ischemic heart worsens survival by increasing ER stress and apoptosis.

Snapshots: Endoplasmic Reticulum Stress in Lipid Metabolism and Cardiovascular Disease

“…The ER is the major organelle involved in lipid metabolism, as the ER contains many relevant enzymes for lipid metabolism. ERS is a potential mechanistic link between excess nutrients and lipid accumulation, which is a crucial event in the development of atherosclerosis (Erbay et al, 2009), MI (Perman et al, 2011), and heart failure .…”

“…Intracellular accumulation of myocardial lipids occurs after MI, which decreases heart function (Schaffer, 2003;Perman et al, 2011). Pig MI promotes the accumulation of cholesteryl esters in the infarct and the peri-infarct myocardium, which is concomitant with enhanced ERS and elevated LDL receptor (LDLR) levels (Drevinge et al, 2013).…”

“…Expression of the VLDL receptor (VLDLR) promotes total TG accumulation and increases mortality in mice by increasing ERS in hypoxic cardiomyocytes and ischemic mouse hearts. ERS and lipid accumulation are diminished in VLDLR knockout mice, followed by improved cardiac lipotoxicity, pathological remodeling, and cardiac function, which suggests that normalizing lipid levels by inhibiting ERS after MI might improve myocardial function and serve as a target for the treatment of cardiac lipotoxicity (Perman et al, 2011). Endogenous H2S levels in serum of DCM patients and DCM rats are significant low.…”

The role of triacylglycerol in cardiac energy provision

“…It binds and internalises VLDL and other apo-E containing lipoproteins, including CM, in concert with LPL and apo-E (see [86][87][88][89] likely provides a significant route of glycerolipid uptake by heart [45] but its dependence on LPL status has been challenged [92], and vldlr -/-mice do not show altered plasma LP levels, despite decreased LPL expression [94], although stressing FA metabolism in these animals by fasting or high fat feeding [95] or cross-breeding on a hyperlipidemic ob/ob [95] or ldlr -/- [96] or lpl -/+ [88] background does reveal a hypertriglyceridemic phenotype. VLDLR may substitute for bulk cardiac TAG uptake in LPL-KO models, and mediate the uptake of lipoprotein remnant (including CM remnant) particles [86,97], again facilitated by LPL and apo-E [87].…”

“…In experimental sepsis, endotoxin decreased both cardiac VLDLR (via IL-1 expression and lipid accumulation in fasting mice; downregulation of VLDLR expression by LPS was mediated by IL-1 [106]. VLDLR is upregulated in hypoxic/ischemic conditions in rodent cardiomyocytes, hearts, and human hearts, via HIF-1 and (non-classical) HRE in the VLDLR promoter [92,107,108] with increased VLDL uptake and myocellular lipid…”