Abstract
Homocysteine (Hcy) has been recognized for the past five decades as a risk factor for atherosclerosis. However, the role of Hcy in the pathological changes associated with atherosclerosis as well as the pathological mechanisms triggered by Hcy accumulation is poorly understood. Due to the reversal of the physiological direction of the reaction catalyzed by S-adenosyl-L-homocysteine hydrolase Hcy accumulation leads to the synthesis of S-adenosyl-L-homocysteine (AdoHcy). AdoHcy is a strong product inhibitor of S-adenosyl-L-methionine (AdoMet)-dependent methyltransferases, and to date more than 50 AdoMet-dependent methyltransferases that methylate a broad spectrum of cellular compounds including nucleic acids, proteins and lipids have been identified. Phospholipid methylation is the major consumer of AdoMet, both in mammals and in yeast. AdoHcy accumulation induced either by Hcy supplementation or due to S-adenosyl-L-homocysteine hydrolase deficiency results in inhibition of phospholipid methylation in yeast. Moreover, yeast cells accumulating AdoHcy also massively accumulate triacylglycerols (TAG). Similarly, Hcy supplementation was shown to lead to increased TAG and sterol synthesis as well as to the induction of the unfolded protein response (UPR) in mammalian cells. In this review a model of deregulation of lipid metabolism in response to accumulation of AdoHcy in Hcy-associated pathology is proposed.
Highlights
The first indication that sulfur amino acid metabolism is linked to atherosclerosis came from observations in 1953 demonstrating that pathogenic cholesterol concentrations and experimental atherogenesis in monkeys can be inhibited by dietary methionine [1]
While PE methylation is the predominant way to synthesize phospholipids in yeast, phospholipid synthesis by the de novo methylation pathway is primarily present in the liver in mammals, where it constitutes 30% of PC production and account for estimated 10 μmol and 1,65 mmol PEMTderived PC secreted into bile per day in mice and humans, respectively [26, 27]
A mechanism of deregulation of lipid metabolism and lipid-associated cellular functions in hyperhomocysteinemia mediated by AdoHcy accumulation and subsequent inhibition of phospholipid methylation is proposed in this paper
Summary
The first indication that sulfur amino acid metabolism is linked to atherosclerosis came from observations in 1953 demonstrating that pathogenic cholesterol concentrations and experimental atherogenesis in monkeys can be inhibited by dietary methionine [1]. Since the early 60s elevated Hcy levels in blood (hyperhomocysteinemia) caused by different deficiencies of sulfur amino acid metabolism were reported to be associated with vascular disease and, in particular, with atherosclerotic plaque formation [2, 3]. Deficiency in phospholipid methylation, but not in the synthesis of PC by the CDP-choline pathway, protects from diet-induced obesity in mice due to increased energy utilization suggesting that PEMT plays a role in whole energy metabolism and is linked to insulin signaling [60]. Sensitivity of phospholipid methylation to AdoHcy accumulation [16, 18, 63] as well as numerous correlations reported for phospholipid methylation pathway suggests that interference with this reaction in Hcy-associated pathology may lead to widespread defects, what seems to be the case. A mechanism of deregulation of lipid metabolism and lipid-associated cellular functions in hyperhomocysteinemia mediated by AdoHcy accumulation and subsequent inhibition of phospholipid methylation is proposed in this paper
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