Elevated S-Adenosylhomocysteine Alters Adipocyte Functionality With Corresponding Changes in Gene Expression and Associated Epigenetic Marks

Abstract

Maternal deficiencies in micronutrients affecting one-carbon metabolism before and during pregnancy can influence metabolic status and the degree of insulin resistance and obesity of the progeny in adulthood. Notably, maternal and progeny plasma S-adenosylhomocysteine (SAH) levels are both elevated after vitamin deficiency in pregnancy. Therefore, we investigated whether this key one-carbon cycle intermediate directly affects adipocyte differentiation and function. We found that expansion and differentiation of murine 3T3-L1 preadipocytes in the presence of SAH impaired both basal and induced glucose uptake as well as lipolysis compared with untreated controls. SAH did not alter preadipocyte factor 1 (Dlk1) or peroxisome proliferator–activated receptor-γ 2 (Pparγ2) but significantly reduced expression of CAAT enhancer-binding protein-α (Cebpα), Cebpβ, and retinoid x receptor-α (Rxrα) compared with untreated adipocytes. SAH increased Rxrα methylation on a CpG unit (chr2:27,521,057+, chr2:27,521,049+) and CpG residue (chr2:27,521,080+), but not Cebpβ methylation, relative to untreated adipocytes. Trimethylated histone H3-Lys27 occupancy was significantly increased on Cebpα and Rxrα promoters in SAH-treated adipocytes, consistent with the reduction in gene expression. In conclusion, SAH did not affect adipogenesis per se but altered adipocyte functionality through epigenetic mechanisms, such that they exhibited altered glucose disposal and lipolysis. Our findings implicate micronutrient imbalance in subsequent modulation of adipocyte function.

Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE −/− Mice

“…Finally, some studies in which cells were treated directly with SAH indicate that SAH might be able to enter cells directly. 31 Although hyperhomocysteinemia is a risk factor for atherosclerosis, the inconsistent results of cohort studies and the negative results of clinical intervention trials suggest that the causal relationship between homocysteine and cardiovascular disease is still controversial. 32,33 However, previous studies have reported that severe hyperhomocysteinemia (>100 μmol/L) accelerated the atherosclerotic progression in animal models, and administration of a superphysiological dose of homocysteine (≈1 mmol/L) increased the pathogenesis of atherosclerosis in cultured cells.…”

Nutrigenomic regulation of adipose tissue development — role of retinoic acid: A review

“…Besides Zfp423, epigenetic regulation of PPARγ and C/EBPα during adipogenesis was also observed (Ngo et al, 2014). The PPARγ2 promoter DNA demethylation was detected during 3T3-L1 adipogenesis (Kamstra et al, 2014).…”

Role of S-adenosylhomocysteine in cardiovascular disease and its potential epigenetic mechanism

“…However, recently Elshorbagy et al (2013) reported that plasma SAM, but not SAH, is independently associated with fat mass and trunk adiposity in older adults. In an in vitro study, Ngo et al (2014) found that expansion and differentiation of murine 3T3-L1 preadipocytes in the presence of SAH impaired both basal and induced glucose uptake and lipolysis compared with untreated controls. However, elevated intracellular SAH did not alter preadipocyte factor 1 and peroxisome proliferator activated receptor ␥ 2 .…”

“…In particular, the histone modification 3meH3K27 has been widely linked to the repression of transcription elongation leading to an inhibition of gene expression (Guenther et al, 2007). In adipocytes undergoing differentiation in the presence of elevated SAH, Ngo et al (2014) found elevated intracellular SAH concentrations significantly reduced the expression of the CAAT enhancer binding proteins (Cebp)˛, Cebpˇ and retinoid x receptor (Rxr)ą nd increased Rxr˛, but not Cebpˇ, methylation. Further, SAH significantly enhanced occupancy of 3meH3K27 on the promoters of Cebp˛ and Rxr˛.…”