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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.