Homocysteine regulates fatty acid and lipid metabolism in yeast

Abstract

S-Adenosyl-l-homocysteine hydrolase (AdoHcy hydrolase; Sah1 in yeast/AHCY in mammals) degrades AdoHcy, a by-product and strong product inhibitor of S-adenosyl-l-methionine (AdoMet)-dependent methylation reactions, to adenosine and homocysteine (Hcy). This reaction is reversible, so any elevation of Hcy levels, such as in hyperhomocysteinemia (HHcy), drives the formation of AdoHcy, with detrimental consequences for cellular methylation reactions. HHcy, a pathological condition linked to cardiovascular and neurological disorders, as well as fatty liver among others, is associated with a deregulation of lipid metabolism. Here, we developed a yeast model of HHcy to identify mechanisms that dysregulate lipid metabolism. Hcy supplementation to wildtype cells up-regulated cellular fatty acid and triacylglycerol content and induced a shift in fatty acid composition, similar to changes observed in mutants lacking Sah1. Expression of the irreversible bacterial pathway for AdoHcy degradation in yeast allowed us to dissect the impact of AdoHcy accumulation on lipid metabolism from the impact of elevated Hcy. Expression of this pathway fully suppressed the growth deficit of sah1 mutants as well as the deregulation of lipid metabolism in both the sah1 mutant and Hcy-exposed wildtype, showing that AdoHcy accumulation mediates the deregulation of lipid metabolism in response to elevated Hcy in yeast. Furthermore, Hcy supplementation in yeast led to increased resistance to cerulenin, an inhibitor of fatty acid synthase, as well as to a concomitant decline of condensing enzymes involved in very long-chain fatty acid synthesis, in line with the observed shift in fatty acid content and composition.

Effect of cadmium on essential metals and their impact on lipid metabolism in Saccharomyces cerevisiae

“…5). This data strongly supports the recent findings of S-adenosyl homocysteine as the key trigger of lipid deregulation (Visram et al 2018). As a response to Cd stress, the host cell's defence mechanism activates UPR transcription factor and UPR genes and proteins (Table 2) (Gardarin et al 2010;Wysocki and Tamás 2010;Rajakumar et al 2016a).…”

“…When cells were subjected to Cd toxicity, MET transcriptional factors like MET4, MET28, MET31, and MET32 were upregulated (Hosiner et al 2014), indicative of significant links to the sulphur and methyl cycle genes (Tables 3 and 4). SAM regulated de novo PC synthesis genes such as CHO2 and OPI3 that controlled the major membrane phospholipids, PC and PE, in both yeast and mammals (Visram et al 2018). Deletion of CHO2 and OPI3 induced lipid alterations including TAG, LD accumulation, increased FA content, and altered FA profiles in yeast (Rajakumar et al 2016a).…”

Associations of the MTHFR rs1801133 polymorphism with coronary artery disease and lipid levels: a systematic review and updated meta-analysis

“…Baszczuk et al [ 42 ] reported that a daily administration of 15 mg of folic acid led to a considerable decrease in homocysteine levels, and a substantive increase in HDL-C levels in the patients with primary hypertension. In yeast cells, homocysteine supplementation increased cellular fatty acid and TG contents, induced a shift in fatty acid composition, and decreased the condensing enzymes involved in very long-chain fatty acid synthesis [ 43 ]. Secondly, the rs1801133 polymorphism may modulate the lipid metabolism by affecting the methylation state of DNA or proteins.…”

Quantitative imaging of lipid droplets in single cells

“…Intracellular LDs store a wide distribution of lipid molecules and lipid metabolism directly alters the lipid composition of LDs. 30,31 The field of lipidomics aims to study changes in lipid metabolism in response to physiological, pathological, and environmental conditions by characterizing this compositional distribution of all cellular lipids.…”