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 Ca2+ 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.
The identification of molecular targets of bioactive food components is important to understand the mechanistic aspect of their physiological functions. Here, we have developed a screening system that enables us to determine the activation of G protein-coupled receptors (GPCRs) by food components and have identified GPR55 as a target for curcumin. Curcumin activated GPR55 and induced serum-response element- and serum-response factor-mediated transcription, which were inhibited by Rho kinase and GPR55 antagonists. Both the methoxy group and the heptadienone moiety of curcumin were required for GPR55 activation. The F1905.47 residue of GPR55 was important for the interaction with curcumin. The curcumin-induced secretion of glucagon-like peptide-1 in GLUTag cells was inhibited by a GPR55 antagonist. These results indicate that expression screening is a useful system to identify GPCRs as targets of food components and strongly suggest that curcumin activates GPR55 as an agonist, which is involved in the physiological function of curcumin.
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