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

Kusu, Hikari; Yoshida, Hiroki; Kudo, Michiko; Okuyama, Mai; Harada, Naoki; Naito, Michitaka; Akagawa, Mitsugu

doi:10.1002/mnfr.201801377

Cited by 19 publications

(12 citation statements)

References 53 publications

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“…Moreover, Kusu et al. (2019) showed that tomatidine‐stimulated activation of AMPK was via CaMKKβ. This study indicated that LKB1 knockdown inhibited the CA‐induced upregulation of AMPKα phosphorylation, which was not suppressed by the CaMkkβ inhibitor, STO‐609, suggesting that the activation of AMPK by CA occurred via LKB1, not CaMKKβ.…”

Section: Resultsmentioning

confidence: 99%

Coniferaldehyde ameliorates the lipid and glucose metabolism in palmitic acid‐induced HepG2 cells via the LKB1/AMPK signaling pathway

Gai

Zhou

Zhang

et al. 2020

Journal of Food Science

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Impaired lipid and glucose metabolism in the liver is a crucial characteristic of nonalcoholic fatty liver disease (NAFLD). Coniferaldehyde (CA), a kind of phenolic compound found in many edible plants, has multiple biological and pharmacological functions. However, since the effect and molecular mechanism of CA on hepatic lipid and glucose metabolism disorders in NAFLD remain unknown, this study investigated its impact on the lipid and glucose metabolism of palmitic acid (PA)‐induced HepG2 cells. Compared with the HepG2 cells treated only with PA, supplementation with 25, 50, and 100 µM CA reduced the levels of intracellular triglyceride (by 7.11%, 19.62%, and 31.57%) and total cholesterol (by 8.46%, 23.32%, and 27.17%), and enhanced glucose uptake (by 40.91%, 57.49%, and 61.32%) and intracellular glycogen content (by 12.75%, 41.27%, and 53.77%). Moreover, CA supplementation downregulated the expression of sterol regulatory element‐binding protein‐1, fatty acid synthase, and stearoyl‐CoA desaturase 1 related to lipogenesis while upregulating the expression of carnitine palmitoyltransferase 1α related to fatty acid oxidation. CA supplementation also upregulated the glucose transporter 2 protein expression and phosphorylation of glycogen synthase kinase 3β while downregulating the phosphorylation of glycogen synthase. Most importantly, most of these effects of CA were reversed by pretreatment with AMP‐activated protein kinase (AMPK) inhibitor and small interfering RNA‐liver kinase B1 (LKB1). In conclusion, CA ameliorated the lipid and glucose metabolism in PA‐induced HepG2 cells via the LKB1/AMPK signaling pathway. Practical Application In this study, coniferaldehyde appeared to be effective in ameliorating hepatic lipid and glucose metabolism disorders in nonalcoholic fatty liver disease by reducing the levels of intracellular triglyceride and total cholesterol and enhancing glucose uptake and intracellular glycogen content via the LKB1/AMPK signaling pathway in vitro. Therefore, our findings provide new evidence in support of that supplementation with coniferaldehyde or food rich in coniferaldehyde might be considered as a viable dietary intervention strategy for preventing and treating nonalcoholic fatty liver disease.

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Section: Resultsmentioning

confidence: 99%

Coniferaldehyde ameliorates the lipid and glucose metabolism in palmitic acid‐induced HepG2 cells via the LKB1/AMPK signaling pathway

Gai

Zhou

Zhang

et al. 2020

Journal of Food Science

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“…It has been reported that tomatidine suppresses high-fat diet-induced increases in body weight and fat accumulation in white adipose tissue [ 23 ]. Additionally, tomatidine suppresses lipid accumulation in HepG2 hepatocytes [ 24 ] and reduces hepatic lipid accumulation in mice fed a high-fat diet, by suppressing the expression of fatty acid synthases and transcription factors involved in lipogenesis [ 23 ]. One might hypothesize that tomatidine-induced changes in lipid metabolism may cause a decrease in body weight.…”

Section: Discussionmentioning

confidence: 99%

The Steroidal Alkaloid Tomatidine and Tomatidine-Rich Tomato Leaf Extract Suppress the Human Gastric Cancer-Derived 85As2 Cells In Vitro and In Vivo via Modulation of Interferon-Stimulated Genes

et al. 2022

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The steroidal alkaloid tomatidine is an aglycone of α-tomatine, which is abundant in tomato leaves and has several biological activities. Tomatidine has been reported to inhibit the growth of cultured cancer cells in vitro, but its anti-cancer activity in vivo and inhibitory effect against gastric cancer cells remain unknown. We investigated the efficacy of tomatidine using human gastric cancer-derived 85As2 cells and its tumor-bearing mouse model and evaluated the effect of tomatidine-rich tomato leaf extract (TRTLE) obtained from tomato leaves. In the tumor-bearing mouse model, tumor growth was significantly inhibited by feeding a diet containing tomatidine and TRTLE for 3 weeks. Tomatidine and TRTLE also inhibited the proliferation of cultured 85As2 cells. Microarray data of gene expression analysis in mouse tumors revealed that the expression levels of mRNAs belonging to the type I interferon signaling pathway were altered in the mice fed the diet containing tomatidine and TRTLE. Moreover, the knockdown of one of the type I interferon-stimulated genes (ISGs), interferon α-inducible protein 27 (IFI27), inhibited the proliferation of cultured 85As2 cells. This study demonstrates that tomatidine and TRTLE inhibit the tumor growth in vivo and the proliferation of human gastric cancer-derived 85As2 cells in vitro, which could be due to the downregulation of ISG expression.

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“…5′-AMP-activated protein kinase catalytic subunit alpha-2 (AMPK) promotes innate immunity and antiviral defense through modulation of STING signaling [ 35 ]. Tomatidine also stimulated AMPK phosphorylation by activating the CaMKKβ pathway [ 36 ]. Tomatidine inhibits dengue virus particle production partly by inhibiting cyclic AMP-dependent transcription factor ATF-4 (ATF4) [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Tomatidine inhibits porcine epidemic diarrhea virus replication by targeting 3CL protease

Wang

Bai

Liu

et al. 2020

Vet Res

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Porcine epidemic diarrhea virus (PEDV) causes lethal diarrhea in suckling piglets, leading to severe economic losses worldwide. There is an urgent need to find new therapeutic methods to prevent and control PEDV. Not only is there a shortage of commercial anti-PEDV drugs, but available commercial vaccines fail to protect against highly virulent PEDV variants. We screened an FDA-approved library of 911 natural products and found that tomatidine, a steroidal alkaloid extracted from the skin and leaves of tomatoes, demonstrates significant inhibition of PEDV replication in Vero and IPEC-J2 cells in vitro. Molecular docking and molecular dynamics analysis predicted interactions between tomatidine and the active pocket of PEDV 3CL protease, which were confirmed by fluorescence spectroscopy and isothermal titration calorimetry (ITC). The inhibiting effect of tomatidine on 3CL protease was determined using cleavage visualization and FRET assay. Tomatidine-mediated blocking of 3CL protease activity in PEDV-infected cells was examined by western blot detection of the viral polyprotein in PEDV-infected cells. It indicates that tomatidine inhibits PEDV replication mainly by targeting 3CL protease. In addition, tomatidine also has antiviral activity against transmissible gastroenteritis virus (TGEV), porcine reproductive and respiratory syndrome virus (PRRSV), encephalo myocarditis virus (EMCV) and seneca virus A (SVA) in vitro. These results may be helpful in developing a new prophylactic and therapeutic strategy against PEDV and other swine disease infections.

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

Cited by 19 publications

References 53 publications

Coniferaldehyde ameliorates the lipid and glucose metabolism in palmitic acid‐induced HepG2 cells via the LKB1/AMPK signaling pathway

Coniferaldehyde ameliorates the lipid and glucose metabolism in palmitic acid‐induced HepG2 cells via the LKB1/AMPK signaling pathway

The Steroidal Alkaloid Tomatidine and Tomatidine-Rich Tomato Leaf Extract Suppress the Human Gastric Cancer-Derived 85As2 Cells In Vitro and In Vivo via Modulation of Interferon-Stimulated Genes

Tomatidine inhibits porcine epidemic diarrhea virus replication by targeting 3CL protease

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