AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver

Liu, Shudong; Jing, Fei; Yu, Chunxiao; Gao, Ling; Qin, Yejun; Zhao, Jiajun

doi:10.1371/journal.pone.0124951

Cited by 58 publications

(60 citation statements)

References 37 publications

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“…This is in agreement with earlier studies demonstrating that AICAR reduces diet-induced hepatic triacylglycerol content in rats [9] and TNF-α-induced intracellular triacylglycerol accumulation in human hepatic HepG2 cell lines [11]. AICAR also attenuated HFD-induced hepatic cholesterol accumulation in Adipoq −/− mice, an interesting finding since AICAR-induced activation of AMPK inhibits the hepatic thyroid stimulating hormone (TSH)/sterol regulatory element-binding protein-2 (SREBP-2)/3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway necessary for cholesterol biosynthesis [10].…”

Section: Discussionmentioning

confidence: 99%

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AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

et al. 2017

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Aims/hypothesis In this study, we aimed to evaluate the therapeutic potential of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase, for ameliorating high-fat diet (HFD)-induced pathophysiology in mice. We also aimed to determine whether the beneficial effects of AICAR were dependent on adiponectin. Furthermore, human adipose tissue was used to examine the effect of AICAR ex vivo. Methods Six-week-old male C57BL/6J wild-type and Adipoq −/− mice were fed a standard-fat diet (10% fat) or an HFD (60% fat) for 12 weeks and given vehicle or AICAR (500 μg/g) three times/week from weeks 4-12. Diet-induced pathophysiology was examined in mice after 11 weeks by IPGTT and after 12 weeks by flow cytometry and western blotting. Human adipose tissue biopsies from obese (BMI 35-50 kg/m 2 ) individuals were incubated with vehicle or AICAR (1 mmol/l) for 6 h at 37°C, after which inflammation was characterised by ELISA (TNF-α) and flow cytometry. Results AICAR attenuated adipose inflammation in mice fed an HFD, promoting an M1-to-M2 macrophage phenotype switch, while reducing infiltration of CD8 + T cells. AICAR treatment of mice fed an HFD partially restored glucose tolerance and attenuated hepatic steatosis and kidney disease, as evidenced by reduced albuminuria (p < 0.05), urinary H 2 O 2 (p < 0.05) and renal superoxide levels (p < 0.01) in both wild-type and Adipoq −/− mice. AICAR-mediated protection occurred independently of adiponectin, as similar protection was observed in wild-type and Adipoq −/− mice. In addition, AICAR promoted an M1-to-M2 macrophage phenotype switch and reduced TNF-α production in tissue explants from obese human patients. Conclusions/interpretation AICAR may promote metabolic health and protect against obesity-induced systemic diseases Catherine Godson and Kumar Sharma are joint senior authors.Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 99%

“…Evidence from experimental models has shown that AICAR may attenuate metabolic [6][7][8], hepatic [9][10][11] and renal pathophysiology [12][13][14][15]. However, the use of AICAR could be compromised as some reports indicate that AICAR increases adiponectin production [13].…”

Section: Introductionmentioning

confidence: 99%

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

et al. 2017

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“…AMPK is a potential modulator of metabolism of lipid accumulations via up-regulation of fatty acid oxidation and down-regulation of lipogenesis, glucose production, and protein synthesis [4]. In view of this information, the effect of YE on AMPK signalling was investigated.…”

Section: Resultsmentioning

confidence: 99%

“…AMPK is a metabolic protein, which plays a central role in lipid metabolism and inhibits anabolic pathways, including cholesterol synthesis by targeting HMGCR [4]. HMGCR is a rate-limiting enzyme in cholesterol synthesis pathway; it is suppressed by cholesterol derived from the degradation of LDL via the LDL receptor [5].…”

Section: Introductionmentioning

confidence: 99%

Citrus junos Tanaka peel ameliorates hepatic lipid accumulation in HepG2 cells and in mice fed a high-cholesterol diet

Shin

Park

Sung

et al. 2016

BMC Complement Altern Med

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Background Citrus junos Tanaka (yuja), a yellow-coloured citrus fruit has traditionally been consumed in Korea, Japan, and China and has been found effective in preventing certain diseases. However, the inhibitory effect of yuja on hepatic lipid accumulation has not been clearly elucidated thus far.MethodsThe inhibitory effect of yuja on hepatic lipid accumulation was investigated in both cell culture and mouse models. We investigated the inhibitory effect of ethanol extract of yuja peel (YE) using HepG2 cells. We next confirmed the effect of YE in mice fed a high cholesterol diet. Animals were divided into 4 groups (n = 8): a normal diet group (ND), a high-cholesterol diet group (HC), high-cholesterol diet plus 1% YE (YL), high-cholesterol diet plus 5% YE (YH).ResultSeventy percent ethanolic extracts of yuja peel (YE) reduced oleic acid-induced hepatic lipid accumulation in HepG2 cells. Treatment with YE at 100, 200 μg/mL up-regulated expression levels of cholesterol metabolism-related proteins such as AMPK, ACC, PPAR-α, and CPT1 and down-regulated the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase. The hypocholesterolemic effect of YE was further confirmed in mice fed a high-cholesterol diet. Compared to ND (normal diet) mice, HC (high-cholesterol diet) mice showed increased body weight, liver fat content, liver weight, and content of total cholesterol and low-density lipoprotein (LDL) cholesterol. On the contrary, administrations of YL (HC + 1% YE) or YH (HC + 5% YE) significantly reduced body weight, liver fat content, liver weight, total cholesterol, and LDL cholesterol compared to those of only HC fed mice group. As a result of in vitro data, protein expressions of PPAR-α and CPT1 were induced in mice fed YE diet compared to HC diet but HMGCR expression was decreased.ConclusionsYuja peel ameliorates hepatic lipid accumulation in both cell culture and mouse models and therefore, could serve as a useful supplement for hypercholesterolemia.

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“…These mice have higher amount of lipids, fatty acids and TG suggesting these animals do not have the metabolic efficiency exhibited by the control mice. Western diet (WD) has been associated with an increase in lipid accumulation in the liver whereas AICAR treatment has been associated with a decrease in lipid accumulation [35][36][37][38][39][40]. WD has been shown to increase oxidative stress and increase fat accumulation in the liver by decreasing fatty acid metabolism resulting in hepatic steatosis.…”

Section: Discussionmentioning

confidence: 99%

The Role of Fatty Acid Metabolism and Apolipoproteins in Ths-Induced Hepatic Steatosis in Mice

Flores¹,

Adhami²,

Martins‐Green³

2017

J Clinic Toxicol

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AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver

Cited by 58 publications

References 37 publications

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

Citrus junos Tanaka peel ameliorates hepatic lipid accumulation in HepG2 cells and in mice fed a high-cholesterol diet

The Role of Fatty Acid Metabolism and Apolipoproteins in Ths-Induced Hepatic Steatosis in Mice

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