Chronic stress or excessive exposure to glucocorticoids (GC) contributes to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Glucocorticoid receptor (GR) mediates the action of GC, but its downstream signalling is not fully understood. Fat mass and obesity associated (FTO) protein and its demethylation substrate N6-methyladenosine (m 6 A) are both reported to participate in the regulation of lipid metabolism, yet it remains unknown whether they are involved in GC-induced hepatic lipid accumulation as new components of GR signalling. In this study, we use both in vivo and in vitro models of GC-induced hepatic lipid accumulation and demonstrate that the activation of lipogenic genes and accumulation of lipid in liver cells are mediated by GR-dependent FTO transactivation and m 6 A demethylation on mRNA of lipogenic genes. Targeted mutation of m 6 A methylation sites and FTO knockdown further validated the role of m 6 A on 3ʹUTR of sterol regulatory element-binding transcription factor 1 and stearoyl-CoA desaturase mRNAs. Finally, FTO knockdown significantly alleviated dexamethasone-induced fatty liver in mice. These results demonstrate a role of GR-mediated FTO transactivation and m 6 A demethylation in the pathogenesis of NAFLD and provide new insight into GR signalling in the regulation of fat metablism in the liver.

Spermidine is an acetyltransferase inhibitor and a specific inducer of autophagy. Recently, spermidine is identified as a potential therapeutic agent for age-related muscle atrophy and inherited myopathies. However, the effect of spermidine on nonpathological skeletal muscle remains unclear. In this study, long-term spermidine administration in mice lowered the mean cross-sectional area of the gastrocnemius muscle and reduced the expression of myosin heavy chain isoforms in the muscle, which was associated with ubiquitination. Moreover, spermidine supplementation induced autophagy in satellite cells and enhanced satellite cell proliferation. ChIP assay revealed that spermidine repressed H3K56ac in the promoter of ACVR2B and lowered the binding affinity of Smad3 to the promoters of Myf5 and MyoD. Altogether, our results indicate that long-term administration of spermidine can activate satellite cells, as well as enhance autophagy, eventually resulting in muscle atrophy. In addition, H3K56ac and Smad3 emerged as key determinants of satellite cell activation.

Excess 2-hydroxy-(4-methylthio)butanoic acid (HMB) supplementation induces hyperhomocysteinemia, which contributes to hepatic cholesterol accumulation. However, it is unclear whether and how high levels of HMB break hepatic cholesterol homeostasis in nursery piglets. In this study, HMB oversupplementation suppressed food intake and decreased body weight in nursery piglets. Hyperhomocysteinemia and higher hepatic cholesterol accumulation were observed in HMB groups. Accordingly, HMB significantly increased the protein content of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and glycine N-methyltransferase (GNMT) but decreased that of acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1). Significant downregulation of miR-150, miR-181d-5p, and miR-296-3p targeting the 3'-untranslated regions (UTRs) of GNMT and HMGCR was detected in the liver of HMB-treated piglets, and their functional validation was confirmed by dual-luciferase reporter assay. Furthermore, hypermethylation of miR-150 promoter was detected in association with suppressed miR-150 expression in the livers of HMB-treated piglets. This study indicated a new mechanism of hepatic cholesterol unhomeostasis by dietary methyl donor supplementation.