Triacylglycerol Accumulation Activates the Mitochondrial Apoptosis Pathway in Macrophages

Abstract

Programmed cell death of lipid-laden macrophages is a prominent feature of atherosclerotic lesions and mostly ascribed to accumulation of excess intracellular cholesterol. The present in vitro study investigated whether intracellular triacylglycerol (TG) accumulation could activate a similar apoptotic response in macrophages. To address this question, we utilized peritoneal macrophages isolated from mice lacking adipose triglyceride lipase (ATGL), the major enzyme responsible for TG hydrolysis in multiple tissues. In Atgl−/− macrophages, we observed elevated levels of cytosolic Ca2+ and reactive oxygen species, stimulated cytochrome c release, and nuclear localization of apoptosis-inducing factor. Fragmented mitochondria prior to cell death were indicative of the mitochondrial apoptosis pathway being triggered as a consequence of defective lipolysis. Other typical markers of apoptosis, such as externalization of phosphatidylserine in the plasma membrane, caspase 3 and poly(ADP-ribose) polymerase cleavage, were increased in Atgl−/− macrophages. An artificial increase of cellular TG levels by incubating wild-type macrophages with very low density lipoprotein closely mimicked the apoptotic phenotype observed in Atgl−/− macrophages. Results obtained during the present study define a novel pathway linking intracellular TG accumulation to mitochondrial dysfunction and programmed cell death in macrophages.

Increased expression of interleukin-1β in triglyceride-induced macrophage cell death is mediated by p38 MAP kinase

“…1). In support of our findings, previous reports have shown that TG stimulates the apoptotic pathway in macrophages (26) and that upregulation of Bcl-2 protects macrophages from apoptosis (27). Taken together, these data strongly suggest that the decrease in macrophage viability after TG treatment was due to activation of the apoptotic pathway.…”

Triglyceride-Induced Macrophage Cell Death Is Triggered by Caspase-1

“…Recently, it has been reported that TG-triggered macrophage cell death is also mediated via a caspase-3/7-dependent apoptotic pathway. 28) It was also reported that caspase-1 is involved in the mitochondrial apoptotic pathway due to activation of caspase-9 and caspase-3. 26) Taken together with our results, we suggest that TG-induced macrophage death is mediated by activation of both the caspase-1-dependent pyroptotic pathway and the caspase-3/7-dependent apoptotic pathway.…”

Depleted Leukocyte Mitochondrial DNA Copy Number in Metabolic Syndrome

“…In an in vivo study, Aflaki et al disclosed a particular pathway related to intracellular triglyceride accumulation that promoted mitochondrial dysfunction with the consequence of programmed cell death in macrophages 19) . Aronis et al stated that exposure to TG provoked down-regulation in mtDNA genomic biogenesis, including Peroxisome proliferator-activated receptor-gamma coactivator-1alpha and nuclear respiratory factor -1, two critical transcription factors to maintain the required mtDNA content 20) .…”