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Introduction:Gan–jiang–ling–zhu (GJLZ) decoction is a classical traditional Chinese medicine prescription. Through invigorating yang, activating qi and dissipating dampness, GJLZ decoction is widely applied for the treatment of chronic digestive disease, including nonalcoholic fatty liver disease. However, efficacy and mechanism of GJLZ decoction behind nonalcoholic steatohepatitis (NASH) treatment remains unelucidated.Methods: NASH was induced in mice, followed by treatment with GJLZ decoction. Various methods including hematoxylin-eosin, oil red O staining, and triglyceride analysis were employed to evaluate the treatment effects of GJLZ decoction on NASH. Gut microbiota, metabolomics, cell viability assays, immunofluorescence and Western blotting were performed to unveil the mechanism behind GJLZ decoction.Results: GJLZ decoction treatment significantly improved hepatic steatosis in mice with NASH. It led to remodeling of gut flora and metabolite structures, including the 12-tridecenoic acid level. 12-Tridecenoic acid aggravated hepatic steatosis by promoting acetyl-coenzyme A carboxylase alpha (ACC) expression and inhibiting carnitine palmitoyltransferase 1A (CPT1A) expression. GJLZ decoction treatment reduced the 12-tridecenoic acid level, inhibited ACC activity and promoted CPT1A expression.Conclusion: Our results demonstrated that 12-tridecenoic acid aggravated hepatic steatosis by affecting the ACC–CPT1A axis and GJLZ decoction treatment effectively reduced the 12-tridecenoic acid level and improved steatosis.

Abstract Background Colorectal carcinoma (CRC) is the third most common cancer and second most common cause of cancer-related deaths worldwide. Ribonucleic acid (RNA) N6-methyladnosine (m6A) and methyltransferase-like 3 (METTL3) play key roles in cancer progression. However, the roles of m6A and METTL3 in CRC progression require further clarification. Methods Adenoma and CRC samples were examined to detect m6A and METTL3 levels, and tissue microarrays were performed to evaluate the association of m6A and METTL3 levels with the survival of patients with CRC. The biological functions of METTL3 were investigated through cell counting kit-8, wound healing, and transwell assays. M6A epitranscriptomic microarray, methylated RNA immunoprecipitation-qPCR, RNA stability, luciferase reporter, and RNA immunoprecipitation assays were performed to explore the mechanism of METTL3 in CRC progression. Results M6A and METTL3 levels were substantially elevated in CRC tissues, and patients with CRC with a high m6A or METTL3 levels exhibited shorter overall survival. METTL3 knockdown substantially inhibited the proliferation, migration, and invasion of CRC cells. An m6A epitranscriptomic microarray revealed that the cell polarity regulator Crumbs3 (CRB3) was the downstream target of METTL3. METTL3 knockdown substantially reduced the m6A level of CRB3, and inhibited the degradation of CRB3 mRNA to increase CRB3 expression. Luciferase reporter assays also showed that the transcriptional level of wild-type CRB3 significantly increased after METTL3 knockdown but not its level of variation. Knockdown of YT521-B homology domain–containing family protein 2 (YTHDF2) substantially increased CRB3 expression. RNA immunoprecipitation assays also verified the direct interaction between the YTHDF2 and CRB3 mRNA, and this direct interaction was impaired after METTL3 inhibition. In addition, CRB3 knockdown significantly promoted the proliferation, migration, and invasion of CRC cells. Mechanistically, METTL3 knockdown activated the Hippo pathway and reduced nuclear localization of Yes1-associated transcriptional regulator, and the effects were reversed by CRB3 knockdown. Conclusions M6A and METTL3 levels were substantially elevated in CRC tissues relative to normal tissues. Patients with CRC with high m6A or METTL3 levels exhibited shorter overall survival, and METTL3 promoted CRC progression. Mechanistically, METTL3 regulated the progression of CRC by regulating the m6A–CRB3–Hippo pathway.

As the predominant type of chronic liver disease, the growing prevalence of nonalcoholic fatty liver disease (NAFLD) has become a concern worldwide. Although obesity plays the most pivotal role in NAFLD, approximately 10–20% of individuals with NAFLD who are not overweight or obese (BMI < 25 kg/m2, or BMI < 23 kg/m2 in Asians) have “lean NAFLD.” Lean individuals with NAFLD have a lower prevalence of diabetes, hypertension, hypertriglyceridemia, central obesity, and metabolic syndrome than nonlean individuals with NAFLD, but higher fibrosis scores and rates of cardiovascular morbidity and all-cause mortality in advanced stages. The pathophysiological mechanisms of lean NAFLD remain poorly understood. Studies have shown that lean NAFLD is more correlated with factors such as environmental, genetic susceptibility, and epigenetic regulation. This review will examine the way in which the research progress and characteristic of lean NAFLD, and explore the function of epigenetic modification to provide the basis for the clinical treatment and diagnosis of lean NAFLD.

Background: As a primarily N6-methyladenosine methyltransferase, methyltransferase 3 (METTL3) plays a crucial role in nonalcoholic fatty liver disease. However, its regulatory mechanism in steatosis remains unknown. Methods: Alpha mouse liver 12 (AML12) cells were induced by free fatty acids (FFA). Triglycerides, lipid droplet assay, and Oil Red O staining were performed to evaluate steatosis. The expression of METTL3 and cytochrome P450 family 4 subfamily f polypeptide 40 (CYP4F40) was measured using Western blotting, real-time quantitative polymerase chain reaction, and dual-luciferase reporter assay. Triglycerides, total cholesterol, almandine aminotransferase, and aspartate aminotransferase were assayed after cinnamaldehyde treatment. Transcriptomics and metabolomics were performed to determine how METTL3 and cinnamaldehyde regulate steatosis. Results: METTL3 protein level was reduced in FFA-induced steatosis in AML12 cells, and METTL3 knockdown aggravated the steatosis. Cinnamaldehyde alleviated steatosis by increasing METTL3 expression. A combined transcriptomics and metabolomics analysis revealed that METTL3 knockdown reduced CYP4F40 expression and reduced the level of capric acid, gamma-linolenic acid, arachidonic acid, and docosapentaenoic acid. Cinnamaldehyde promoted CYP4F40 expression by increasing METTL3 and increased the levels of capric acid, gamma-linolenic acid, arachidonic acid, and docosapentaenoic acid. Finally, the beneficial effects of cinnamaldehyde on steatosis were reversed after METTL3 knockdown. Conclusions: METTL3 knockdown aggravated steatosis in AML12 cells through CYP4F40-mediated fatty acid metabolism, and cinnamaldehyde alleviated steatosis via the METTL3-CYP4F40 pathway.

Nonalcoholic fatty liver disease (NAFLD) is a general term for a series of liver diseases including simple steatosis, non-alcoholic steatohepatitis, liver fibrosis, which is closely related to metabolic syndrome. The pathogenesis of NAFLD is relatively complex, which has gradually changed from the previous 'two-hit' hypothesis to the current ''multiple hits'' hypothesis. However, there is currently no approved treatment for NAFLD in clinic, highlighting the urgent need for drug development. Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor superfamily, whose different subtypes have been proved to regulate different stages of NAFLD, thus becoming promising drug targets for NAFLD. As important sources of drug development, natural products have been proven to treat NAFLD through multiple pathways and multiple targets. In this paper, we outline the regulatory role of PPARs in NAFLD, and summarize some natural products that target PPARs to ameliorate NAFLD, in order to provide reference for drug development of NAFLD.