Tomatidine Reduces Palmitate‐Induced Lipid Accumulation by Activating AMPK via Vitamin D Receptor‐Mediated Signaling in Human HepG2 Hepatocytes

Scope Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide, defined by hepatic over‐accumulation of lipids without significant ethanol consumption. Pharmacological or bioactive food ingredients that suppress hepatic lipid accumulation through AMP‐activated protein kinase (AMPK) signaling, which plays a critical role in the regulation of lipid metabolism, are searched. Methods and results It is found that tomatidine, the aglycone of α‐tomatine abundant in green tomatoes, significantly inhibits palmitate‐provoked lipid accumulation and stimulates phosphorylation of AMPK and acetyl‐CoA carboxylase 1 (ACC1) in human HepG2 hepatocytes. The results also indicate that tomatidine can enhance triglyceride turnover and decline in lipogenesis by upregulating adipose triglyceride lipase (ATGL) and downregulating fatty acid synthase (FAS) via the AMPK signaling‐dependent regulation of transcription factors, element‐binding protein‐1c (SREBP‐1c) and forkhead box protein O1 (FoxO1). Furthermore, mechanistic studies demonstrate that tomatidine‐stimulated AMPK phosphorylation is due to CaMKKβ activation in response to an increase in intracellular Ca 2+ concentration. Finally, it is discovered that tomatidine functions as an agonist for vitamin D receptor to elicit AMPK‐dependent suppression of lipid accumulation. Conclusion The in vitro study suggests the potential efficacy of tomatidine as a preventive and therapeutic treatment in obesity‐related fatty liver diseases.