Strain‐dependent dysregulation of one‐carbon metabolism in male mice is associated with choline‐ and folate‐deficient diet‐induced liver injury

Abstract

Dysregulation of one-carbon metabolism-related metabolic processes is a major contributor to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). It is well established that genetic and gender-specific variations in one-carbon metabolism contribute to the vulnerability to NAFLD in humans. To examine the role of one-carbon metabolism dysregulation in the pathogenesis and individual susceptibility to NAFLD, we used a "population-based" mouse model where male mice from 7 inbred were fed a choline- and folate-deficient (CFD) diet for 12 wk. Strain-dependent down-regulation of several key one-carbon metabolism genes, including methionine adenosyltransferase 1α (Mat1a), cystathionine-β-synthase (Cbs), methylenetetrahydrofolate reductase (Mthfr), adenosyl-homocysteinase (Ahcy), and methylenetetrahydrofolate dehydrogenase 1 (Mthfd1), was observed. These changes were strongly associated with interstrain variability in liver injury (steatosis, necrosis, inflammation, and activation of fibrogenesis) and hyperhomocysteinemia. Mechanistically, the decreased expression of Mat1a, Ahcy, and Mthfd1 was linked to a reduced level and promoter binding of transcription factor CCAAT/enhancer binding protein β (CEBPβ), which directly regulates their transcription. The strain specificity of diet-induced dysregulation of one-carbon metabolism suggests that interstrain variation in the regulation of one-carbon metabolism may contribute to the differential vulnerability to NFLD and that correcting the imbalance may be considered as preventive and treatment strategies for NAFLD.

Modeling progressive non-alcoholic fatty liver disease in the laboratory mouse

“…Methionine deficiency alone can cause fibrotic NASH, while choline deficiency cannot, though it does significantly increase the extent of steatosis in the context of methionine deficiency (Caballero et al 2010). Co-deficiency of dietary choline and folate results in NAFLD that variably progresses to NASH and fibrosis depending on strain background (Pogribny et al 2013). …”

“…Several studies have demonstrated profound interstrain variability in hepatic phenotypes induced by liver damaging treatments (Hill-Baskin et al 2009; Kahle et al 2013; Montgomery et al 2013; Pogribny et al 2013; Shockley et al 2009; Tryndyak et al 2012; Yamazaki et al 2008). Similar gene-environment interactions undoubtedly factor into the pathogenesis of human NAFLD.…”

Interstrain differences in the progression of nonalcoholic steatohepatitis to fibrosis in mice are associated with altered hepatic iron metabolism

“…The level of α-smooth muscle actin (α-SMA) in formalin-fixed, paraffin-embedded liver sections was determined by immunohistochemical staining as described previously [15]. The levels of nonheme iron were determined by histochemical staining using a modified Perls method [23].…”

“…In our previous studies [14,15], we demonstrated that feeding mice a choline-and folate-deficient (CFD) diet for 12 weeks caused liver injury that resembled morphological features of NAFLD in humans; however, the magnitude of liver injury was strain-specific and varied among strains. This interstrain variability in severity of NASH-like liver damage was associated with a marked dysregulation of hepatic lipid and one-carbon metabolism, and the induction of oxidative and endoplasmic reticulum stress [14,15].…”

Maternal Nutrition and Epigenetic Perturbation: Modeling Trends to Translation

“…Alternatively, the role of as yet unidentified loci has been investigated. Choline and folate deficiency were shown to result in mouse strain dependent effects on expression at several one-carbon metabolism genes [55], lipid metabolism genes, and markers of oxidative stress [56]. While the effect on one-carbon metabolism genes implies potential downstream DNA methylation defects and strain dependent effects strongly indicate the involvement of genetic factors, specific epigenetic effects and genetic elements were not investigated.…”