Natural alkaloid bouchardatine ameliorates metabolic disorders in high‐fat diet‐fed mice by stimulating the sirtuin 1/liver kinase B‐1/AMPK axis

Rao, Yong; Yu, Hong; Gao, Lin; Lu, Yuting; Zhao, Xu; Liu, Hong; Gu, Lian‐Quan; Ye, Ji-Ming; Huang, Zhi‐Shu

doi:10.1111/bph.13855

Cited by 35 publications

(31 citation statements)

References 63 publications

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“…Our data suggest the possibility that NecB can be selected as a therapeutic candidate for preventing aging-related diseases. Since the SIRT1, AMPK, and mTOR pathways have been implicated in aging and age-related diseases [13,18,32], we focused on these three pathways to elucidate the molecular mechanism of NecB effect on old HDFs.…”

Section: Discussionmentioning

confidence: 99%

Nectandrin B-mediated activation of the AMPK pathway prevents cellular senescence in human diploid fibroblasts by reducing intracellular ROS levels

Jang

Yang

et al. 2019

Aging

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Nectandrin B (NecB) is a bioactive lignan compound isolated from Myristica fragrans (nutmeg), which functions as an activator of AMP-activated protein kinase (AMPK). Because we recently found that treatment with NecB increased the cell viability of old human diploid fibroblasts (HDFs), the underlying molecular mechanism was investigated. NecB treatment in old HDFs reduced the activity staining of senescence-associated β-galactosidase and the levels of senescence markers, such as the Ser 15 phosphorylated p53, caveolin-1, p21 waf1 , p16 ink4a , p27 kip1 , and cyclin D1. NecB treatment increased that in S phase, indicating a enhancement of cell cycle entry. Interestingly, NecB treatment ameliorated age-dependent activation of AMPK in old HDFs. Moreover, NecB reversed the age-dependent expression and/or activity changes of certain sirtuins (SIRT1−5), and cell survival/death-related proteins. The transcriptional activity of Yin-Yang 1 and the expression of downstream proteins were elevated in NecB-treated old HDFs. In addition, NecB treatment exerted a radical scavenging effect in vitro , reduced cellular ROS levels, and increased antioxidant enzymes in old HDFs. Moreover, NecB-mediated activation of the AMPK pathway reduced intracellular ROS levels. These results suggest that NecB-induced protection against cellular senescence is mediated by ROS-scavenging through activation of AMPK. NecB might be useful in ameliorating age-related diseases and extending human lifespan.

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Section: Discussionmentioning

confidence: 99%

Nectandrin B-mediated activation of the AMPK pathway prevents cellular senescence in human diploid fibroblasts by reducing intracellular ROS levels

Jang

Yang

et al. 2019

Aging

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“…This was essentially based on the protocols used in our recent studies (Rao et al, ). Liver samples or cells were lysed in ice‐cold RIPA extract buffer (Beyotime, Cat# P0013C, Chengdu, China) supplemented with a mixture of protease inhibitors (Roche, Cat# 4693006001, Guangzhou, China).…”

Section: Methodsmentioning

confidence: 99%

“…This was essentially based on the protocols used in our recent studies (Rao et al, 2017). Liver samples or cells were lysed in ice-cold RIPA…”

Section: Immunoblottingmentioning

confidence: 99%

“…This compound, R17, (Figure a; MW373.4) was synthesized by us (Chen et al, ), based on the structure of bouchardatine, an alkaloid isolated from Bouchardatia neurococca (Rutaecae). Bouchardatine itself ameliorated obesity, insulin resistance, and simple hepatic steatosis (triglyceride [TG] accumulation) in mice on a high‐fat (HF) diet, by activating the SIRT1/liver kinase B1 (LKB1)‐AMP‐activated protein kinase (AMPK) axis (Rao et al, ). However, that study did not examine the other characteristics of NAFLD/NASH, such as hepatic inflammation, injury, and fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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Bouchardatine analogue alleviates non‐alcoholic hepatic fatty liver disease/non‐alcoholic steatohepatitis in high‐fat fed mice by inhibiting ATP synthase activity

Rao

et al. 2019

British J Pharmacology

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Background and Purpose Non‐alcoholic hepatic fatty liver disease (NAFLD) is a manifestation of the metabolic syndrome in the liver and non‐alcoholic steatohepatitis (NASH) represents its advanced stage. R17 derived from bouchardatine, shows benefits in the metabolic syndrome, but has not been tested in the liver. The present study examined the pharmacological effects of R17 in a model of NAFLD/NASH and its mode of action. Experimental Approach The effects of R17 were examined in mice fed a high‐fat (HF) diet to induce the pathological characteristics of NAFLD/NASH and in cultures of HuH7 cells. We used histological and immunohistochemical techniques along with western blotting and siRNA. Generation of ROS and apoptosis were measured. Key Results Administration of R17 (20 mg·kg−1, i.p. every other day) for 5 weeks reversed HF‐induced hepatic triglyceride content, inflammation (inflammatory cytokines and macrophage numbers), injury (hepatocyte ballooning and apoptosis, plasma levels of alanine aminotransferase and aspartate aminotransferase), and fibrogenesis (collagen deposition and mRNA expression of fibrosis markers). In cultured cells, R17 reduced cell steatosis from both lipogenesis and fatty acid influx. The attenuated inflammation and cell injury were associated with inhibition of both endoplasmic reticulum (ER) stress and oxidative stress. Notably, R17 activated the liver kinase B1‐AMP‐activated protein kinase (AMPK) pathway by inhibiting activity of ATP synthase, rather than direct stimulation of AMPK. Conclusion and Implications R17 has therapeutic potential for NAFLD/NASH. Its mode of action involves the elimination of ER and oxidative stresses, possibly via activating the LKB1‐AMPK axis by inhibiting the activity of ATP synthase.

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“…It was reported that SIRT1 plays a critical role in lipid metabolism by modulating the activity of transcription factors [14]. In mice and obese patients fed with a high-fat diet, the activity and expression of SIRT1 were significantly decreased, which attenuated the mobilization of fatty acids and promoted the occurrence of metabolic disorders [15][16][17]. In addition, mounting evidence indicates that a long-term, high-calorie-diet induced liver steatosis is promoted by increasing the expression of SIRT1 in animals [18,19].…”

Section: Introductionmentioning

confidence: 99%

Low Expression of Sirtuin 1 in the Dairy Cows with Mild Fatty Liver Alters Hepatic Lipid Metabolism

Zou

Ding

et al. 2020

Animals

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Dairy cows usually experience negative energy balance coupled with an increased incidence of fatty liver during the periparturient period. The purpose of this study was to investigate the effect of hepatic steatosis on the expression of the sirtuin 1 (SIRT1), along with the target mRNA and protein expressions and activities related to lipid metabolism in liver tissue. Control cows (n = 6, parity 3.0 ± 2.0, milk production 28 ± 7 kg/d) and mild fatty liver cows (n = 6, parity 2.3 ± 1.5, milk production 20 ± 6 kg/d) were retrospectively selected based on liver triglycerides (TG) content (% wet liver). Compared with the control group, fatty liver cows had greater concentrations of cholesterol and TG along with the typically vacuolated appearance and greater lipid droplets in the liver. Furthermore, fatty liver cows had greater mRNA and protein abundance related to hepatic lipid synthesis proteins sterol regulatory element binding proteins (SREBP-1c), long-chain acyl-CoA synthetase (ACSL), acyl-CoA carbrolase (ACC) and fatty acid synthase (FAS) and lipid transport proteins Liver fatty acid binding protein (L-FABP), apolipoprotein E (ApoE), low density lipoprotein receptor (LDLR) and microsomal TG transfer protein (MTTP) (p < 0.05). However, they had lower mRNA and protein abundance associated with fatty acid β-oxidation proteins SIRT1, peroxisome proliferator-activated receptor co-activator-1 (PGC-1α), peroxisome proliferator–activated receptor-α (PPARα), retinoid X receptor (RXRα), acyl-CoA 1 (ACO), carnitine palmitoyltransferase 1 (CPT1), carnitine palmitoyltransferase 2 (CPT2) and long- and medium-chain 3-hydroxyacyl-CoA dehydrogenases (LCAD) (p < 0.05). Additionally, mRNA abundance and enzyme activity of enzymes copper/zinc superoxide dismutase (Cu/Zn SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and manganese superoxide dismutase (Mn SOD) decreased and mRNA and protein abundance of p45 nuclear factor-erythroid 2 (p45 NF-E2)-related factor 1 (Nrf1), mitochondrial transcription factor A (TFAM) decreased (p < 0.05). Lower enzyme activities of SIRT1, PGC-1α, Cu/Zn SOD, CAT, GSH-Px, SREBP-1c and Mn SOD (p < 0.05) and concentration of reactive oxygen species (ROS) were observed in dairy cows with fatty liver. These results demonstrate that decreased SIRT1 associated with hepatic steatosis promotes hepatic fatty acid synthesis and inhibits fatty acid β-oxidation. Hence, SIRT1 may represent a novel therapeutic target for the treatment of the fatty liver disease in dairy cows.

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Natural alkaloid bouchardatine ameliorates metabolic disorders in high‐fat diet‐fed mice by stimulating the sirtuin 1/liver kinase B‐1/AMPK axis

Abstract: Bou may have therapeutic potential for obesity-related metabolic diseases by increasing the capacity of energy expenditure in adipose tissues and liver through a mechanism involving the SIRT1-LKB1-AMPK axis.

Cited by 35 publications

References 63 publications

Nectandrin B-mediated activation of the AMPK pathway prevents cellular senescence in human diploid fibroblasts by reducing intracellular ROS levels

Nectandrin B-mediated activation of the AMPK pathway prevents cellular senescence in human diploid fibroblasts by reducing intracellular ROS levels

Bouchardatine analogue alleviates non‐alcoholic hepatic fatty liver disease/non‐alcoholic steatohepatitis in high‐fat fed mice by inhibiting ATP synthase activity

Low Expression of Sirtuin 1 in the Dairy Cows with Mild Fatty Liver Alters Hepatic Lipid Metabolism

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