Abstract
The efficacy of α-cubebenoate isolated from Schisandra chinensis has been previously studied in three disease areas, namely inflammation, sepsis, and allergy, and its role in other diseases is still being explored. To identify the novel function of α-cubebenoate on lipid metabolism and related inflammatory response, alterations in fat accumulation, lipogenesis, lipolysis, and inflammasome activation were measured in 3T3-L1 preadipocytes and primary adipocytes treated with α-cubebenoate. Lipid accumulation significantly decreased in MDI (3-isobutyl-1-methylxanthine, dexamethasone, and insulin)-stimulated 3T3-L1 adipocytes treated with α-cubebenoate without any significant cytotoxicity. The mRNA levels of peroxisome proliferator-activated receptor (PPAR)γ and CCAAT-enhancer binding protein (C/EBP) α for adipogenesis, as well as adipocyte fatty acid binding protein 2 (aP2) and fatty acid synthetase (FAS) for lipogenesis, were reduced after α-cubebenoate treatment, while cell cycle arrest at G2/M stage was restored in the same group. α-cubebenoate treatment induced glycerol release in primary adipocytes and enhanced expression of lipolytic proteins (HSL, perilipin, and ATGL) expression in MDI-stimulated 3T3-L1 adipocytes. Inflammasome activation and downstream cytokines expression were suppressed with α-cubebenoate treatment, but the expression of insulin receptor signaling factors was remarkably increased by α-cubebenoate treatment in MDI-stimulated 3T3-L1 adipocytes. These results indicate that α-cubebenoate may play a novel role as lipogenesis inhibitor, lipolysis stimulator, and inflammasome suppressor in MDI-stimulated 3T3-L1 adipocytes. Our results provide the possibility that α-cubebenoate can be considered as one of the candidates for obesity management.
Highlights
Schisandra chinensis is a plant with significant beneficial effects on various human diseases including cancer, obesity, aging, inflammation, cardiovascular diseases and neurodegenerative disorders based on the function of chemical constituents such as the lignans schisandrin, deoxyschizandrin, gomisins, and pregomisin [1,2]. α-cubebenoate was first identified in the fruits of S. chinensis through a series of extraction processes using various solvents including ethyl alcohol (EtOH), chloroform (CHCl3 ), methyl alcohol (MeOH) and hexane [3]
Remarkable suppression was observed on the expression levels of acid binding protein 2 (aP2) mRNA post α-cubebenoate treatment (Figure 3C). These results suggest that the inhibitory effect of α-cubebenoate on lipid accumulation could be closely linked to the inhibition of transcription of the adipogenic transcription factors (PPARγ and C/EBPα) and the lipogenic proteins
Our results provide scientific evidence that α-cubebenoate inhibits lipogenesis through its effects on the expression of adipogenic factors and cell cycle arrest, while it stimulates lipolysis via the regulation of major lipid droplet-associated proteins in differentiated adipocytes
Summary
Schisandra chinensis is a plant with significant beneficial effects on various human diseases including cancer, obesity, aging, inflammation, cardiovascular diseases and neurodegenerative disorders based on the function of chemical constituents such as the lignans schisandrin, deoxyschizandrin, gomisins, and pregomisin [1,2]. α-cubebenoate was first identified in the fruits of S. chinensis through a series of extraction processes using various solvents including ethyl alcohol (EtOH), chloroform (CHCl3 ), methyl alcohol (MeOH) and hexane [3]. A few studies have elucidated the beneficial role of α-cubebenoate in diseases. This molecule significantly inhibited expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, and production of nitric oxide (NO) and prostaglandin. The α-cubebenoate treated cecal ligation and puncture (CLP) experimental model showed enhanced survival, blocked CLP-induced lung inflammation, and increased bactericidal activity. Α-cubebenoate treatment resulted in reduction of cytokines such as interleukin (IL)-1β and IL-6 as well as attenuation of apoptosis and caspase-3 activation in lymphocyte [4]. Α-cubebenoate suppressed bronchiolar structural changes, accumulation of immune cells and expression of T helper (Th) 2 cytokines induced by ovalbumin challenge in RBL-2H3 mast cells and albino, laboratory-bred strain of the house mice (BALB/c) sensitized with ovalbumin [5]. To date, no studies have provided any scientific evidence on the therapeutic effects of α-cubebenoate on lipid metabolism in adipocytes
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