Nonalcoholic steatohepatitis (NASH) is a key step in the progression of nonalcoholic fatty liver (NAFL) to cirrhosis. However, the molecular mechanisms of the NAFL-to-NASH transition are largely unknown. Here, we identify methyltransferase like 3 (METTL3) as a key negative regulator of NASH pathogenesis. Hepatocyte-specific deletion of Mettl3 drives NAFL-to-NASH progression by increasing CD36-mediated hepatic free fatty acid uptake and CCL2-induced inflammation, which is due to increased chromatin accessibility in the promoter region of Cd36 and Ccl2. Antibody blockade of CD36 and CCL2 ameliorates NASH progression in hepatic Mettl3 knockout mice. Hepatic overexpression of Mettl3 protects against NASH progression by inhibiting the expression of CD36 and CCL2. Mechanistically, METTL3 directly binds to the promoters of the Cd36 and Ccl2 genes and recruits HDAC1/2 to induce deacetylation of H3K9 and H3K27 in their promoters, thus suppressing Cd36 and Ccl2 transcription. Furthermore, METTL3 is translocated from the nucleus to the cytosol in NASH, which is associated with CDK9-mediated phosphorylation of METTL3. Our data reveal a mechanism by which METTL3 negatively regulates hepatic Cd36 and Ccl2 gene transcription via a histone modification pathway for protection against NASH progression.

Brown adipose tissue (BAT) undergoes rapid postnatal development and then protects against cold and obesity into adulthood. However, the molecular mechanism that determines postnatal development and maturation of BAT is largely unknown. Here we show that METTL3 (a key RNA methyltransferase) expression increases significantly in interscapular brown adipose tissue (iBAT) after birth and plays an essential role in the postnatal development and maturation of iBAT. BAT-specific deletion of Mettl3 severely impairs maturation of BAT in vivo by decreasing m⁶A modification and expression of Prdm16, Pparg, and Ucp1 transcripts, which leads to a marked reduction in BAT-mediated adaptive thermogenesis and promotes high-fat diet (HFD)-induced obesity and systemic insulin resistance. These data demonstrate that METTL3 is an essential regulator that controls iBAT postnatal development and energy homeostasis.

Maintaining glucose and lipid homeostasis is crucial for health, with dysregulation leading to metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction–associated fatty liver disease (MAFLD). This study identifies alkylation repair homolog protein 5 (ALKBH5), an RNA N ⁶ -methyladenosine (m ⁶ A) demethylase, as a major regulator in metabolic disease. ALKBH5 is up-regulated in the liver during obesity and also phosphorylated by protein kinase A, causing its translocation to the cytosol. Hepatocyte-specific deletion of Alkbh5 reduces glucose and lipids by inhibiting the glucagon receptor (GCGR) and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. Targeted knockdown of hepatic Alkbh5 reverses T2DM and MAFLD in diabetic mice, highlighting its therapeutic potential. This study unveils a regulatory mechanism wherein ALKBH5 orchestrates glucose and lipid homeostasis by integrating the GCGR and mTORC1 pathways, providing insight into the regulation of metabolic diseases.

Islet β cell death has been proved to contribute to diabetes. Studies suggest that the activation of nuclear factor κB (NF-κB)-inducing kinase (NIK) is involved in the β cell dysfunction encountered in obesity. However, the pathological significance of NIK activation in diabetes remains largely unknown. Here, we report that β cell-specific overexpression of NIK (β-NIK-OE) results in spontaneous diabetes in male mice at a young age (≥10 weeks of age), which is likely due to insulin deficiency, β cell death, and insulitis. Importantly, inhibiting the kinase activation of NIK by the small molecule B022 prevents NIK- or H₂O₂-induced β cell death and also reduces streptozotocin (STZ)-induced β cell death while ameliorating hyperglycemia, suggesting that the kinase activity of NIK is essential in inducing islet inflammation, β cell death, and diabetes. In all, this study not only uncovers a role of NIK in β cell failure but also provides a potential therapeutic target for the treatment of diabetes.

Ectopic lipid accumulation and inflammation are the essential signs of NASH. However, the molecular mechanisms of ectopic lipid accumulation and inflammation during NASH progression are not fully understood. Here we reported that hepatic Wilms' tumor 1-associating protein (WTAP) is a key integrative regulator of ectopic lipid accumulation and inflammation during NASH progression. Hepatic deletion ofWtapleads to NASH due to the increased lipolysis in white adipose tissue, enhanced hepatic free fatty acids uptake and induced inflammation, all of which are mediated by IGFBP1, CD36 and cytochemokines such as CCL2, respectively. WTAP binds to specific DNA motifs which are enriched in the promoters and suppresses gene expression (e.g.,Igfbp1,Cd36andCcl2) with the involvement of HDAC1. In NASH, WTAP is tranlocated from nucleus to cytosol, which is related to CDK9-mediated phosphorylation. These data uncover a mechanism by which hepatic WTAP regulates ectopic lipid accumulation and inflammation during NASH progression.