Role of the AMPK/SIRT1 pathway in non‑alcoholic fatty liver disease (Review)

Anggreini, Putri; Kuncoro, Hadi; Sumiwi, Sri Adi; Levita, Jutti

doi:10.3892/mmr.2022.12922

Cited by 9 publications

(5 citation statements)

References 106 publications

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“…AMPK is an energy regulatory protein that senses cellular energy needs and maintains cellular energy homeostasis 33 . SRT1, an activator of AMPK, increases AMPK phosphorylation and regulates lipid synthesis in fatty liver cells 34 . ACC is a key enzyme of fatty acid synthesis and can induce FAS expression.…”

Section: Discussionmentioning

confidence: 99%

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Gypenoside XIII regulates lipid metabolism in HepG2 hepatocytes and ameliorates nonalcoholic steatohepatitis in mice

Cheng,

Liou,

et al. 2024

The Kaohsiung J of Med Scie

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Gypenoside XIII is isolated from Gynostemma pentaphyllum (Thunb.) Makino. In mice, G. pentaphyllum extract and gypenoside LXXV have been shown to improve non‐alcoholic steatohepatitis (NASH). This study investigated whether gypenoside XIII can regulate lipid accumulation in fatty liver cells or attenuate NASH in mice. We used HepG2 hepatocytes to establish a fatty liver cell model using 0.5 mM oleic acid. Fatty liver cells were treated with different concentrations of gypenoside XIII to evaluate the molecular mechanisms of lipid metabolism. In addition, a methionine/choline‐deficient diet induced NASH in C57BL/6 mice, which were given 10 mg/kg gypenoside XIII by intraperitoneal injection. In fatty liver cells, gypenoside XIII effectively suppressed lipid accumulation and lipid peroxidation. Furthermore, gypenoside XIII significantly increased SIRT1 and AMPK phosphorylation to decrease acetyl‐CoA carboxylase phosphorylation, reducing fatty acid synthesis activity. Gypenoside XIII also decreased lipogenesis by suppressing sterol regulatory element‐binding protein 1c and fatty acid synthase production. Gypenoside XIII also increased lipolysis and fatty acid β‐oxidation by promoting adipose triglyceride lipase and carnitine palmitoyltransferase 1, respectively. In an animal model of NASH, gypenoside XIII effectively decreased the lipid vacuole size and number and reduced liver fibrosis and inflammation. These findings suggest that gypenoside XIII can regulate lipid metabolism in fatty liver cells and improve liver fibrosis in NASH mice. Therefore, gypenoside XIII has potential as a novel agent for the treatment of NASH.

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Section: Discussionmentioning

confidence: 99%

“…33 SRT1, an activator of AMPK, increases AMPK phosphorylation and regulates lipid synthesis in fatty liver cells. 34 ACC is a key enzyme of fatty acid synthesis and can induce FAS expression. AMPK phosphorylation can transfer phosphate to substrate ACC.…”

Section: Effect Of Gypenoside XIII On Liver Inflammation In Mcd Diet-...mentioning

confidence: 99%

Gypenoside XIII regulates lipid metabolism in HepG2 hepatocytes and ameliorates nonalcoholic steatohepatitis in mice

Cheng,

Liou,

et al. 2024

The Kaohsiung J of Med Scie

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“…AMPK is a key modulator of ACC activation. AMPK signaling pathway plays an important role in ameliorating NAFLD and also regulates mitochondrial homeostasis and promotes autophagy, which is related to insulin resistance (Anggreini et al 2023 ; Fang et al 2022 ; Wang et al 2022a ). Metformin inhibits hepatic gluconeogenesis through AMPK-dependent regulation of orphan nuclear receptor small heterodimer partner(Kim et al 2008 ).…”

Section: Discussionmentioning

confidence: 99%

Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis

Guo,

Yan,

Cui

et al. 2023

Mol Med

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Background Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD involves multiple biological changes, including insulin resistance, oxidative stress, inflammation, as well as genetic and environmental factors. Liraglutide has been used to control blood sugar. But the impact of liraglutide on T2DM-associated NAFLD remains unclear. In this study, we investigated the impact and potential molecular mechanisms of inhibiting ferroptosis for liraglutide improves T2DM-associated NAFLD. Methods Mice were fed on high-fat-diet and injected with streptozotocin to mimic T2DM-associated NAFLD and gene expression in liver was analysed by RNA-seq. The fast blood glucose was measured during the period of liraglutide and ferrostatin-1 administration. Hematoxylin and eosin staining was used to evaluate the pathological changes in the liver. The occurrence of hepatic ferroptosis was measured by lipid peroxidation in vivo. The mechanism of liraglutide inhibition ferroptosis was investigated by in vitro cell culture. Results Liraglutide not only improved glucose metabolism, but also ameliorated tissue damage in the livers. Transcriptomic analysis indicated that liraglutide regulates lipid metabolism related signaling including AMPK and ACC. Furthermore, ferroptosis inhibitor rather than other cell death inhibitors rescued liver cell viability in the presence of high glucose. Mechanistically, liraglutide-induced activation of AMPK phosphorylated ACC, while AMPK inhibitor compound C blocked the liraglutide-mediated suppression of ferroptosis. Moreover, ferroptosis inhibitor restored liver function in T2DM mice in vivo. Conclusions These findings indicate that liraglutide ameliorates the T2DM-associated NAFLD, which possibly through the activation of AMPK/ACC pathway and inhibition of ferroptosis.

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“…People with fatty liver disease are prone to suffer vascular risk and cardiovascular disease progression. 2 The Food and Drug Administration (FDA)-approved drug for NAFLD is limited. 3 Therefore, finding new drugs for NAFLD therapy is challenging.…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking Study of Phytosterols in Lygodium microphyllum Towards SIRT1 and AMPK, the in vitro Brine Shrimp Toxicity Test, and the Phenols and Sterols Levels in the Extract

Anggreini,

Kuncoro,

Sumiwi

et al. 2023

JEP

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Background Lygodium microphyllum is a fern plant with various pharmacological activities, and phytosterols were reported contained in the n-hexane and ethyl acetate extract of this plant. Phytosterols are known to inhibit steatosis, oxidative stress, and inflammation. Sirtuin 1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK) are the key proteins that control lipogenesis. However, information about L. microphyllum on SIRT1 and AMPK is still lacking. Purpose This study aims to investigate the binding mode of phytosterols in L. microphyllum extract towards AMPK and SIRT1, and the toxicity of the extract against brine shrimp ( Artemia salina ) larvae, and to determine the phenols and sterols levels in the extract. Methods The molecular docking was performed towards SIRT1 and AMPK using AutoDock v4.2.6, the toxicity of the extract was assayed against brine shrimp ( Artemia salina ) larvae, and the phytosterols were analyzed by employing a thin layer chromatography densitometry, and the total phenols were by spectrophotometry. Results The molecular docking study revealed that β-sitosterol and stigmasterol could occupy the active allosteric-binding site of SIRT1 and AMPK by binding to important residues similar to the protein’s activators. The cold extraction of the plant yields 15.86% w/w. Phytochemical screening revealed the presence of phenols, steroids, flavonoids, alkaloids, and saponins. The total phenols are equivalent to 126 mg gallic acid (GAE)/g dry extract, the total sterols are 954.04 µg/g, and the β-sitosterol level is 283.55 µg/g. The LC 50 value of the extract towards A. salina larvae is 203.704 ppm. Conclusion Lygodium microphyllum extract may have the potential to be further explored for its pharmacology activities, particularly in the discovery of plant-based anti-dyslipidemic drug candidates. However, further studies are needed to confirm their roles in alleviating lipid disorders.

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Role of the AMPK/SIRT1 pathway in non‑alcoholic fatty liver disease (Review)

Cited by 9 publications

References 106 publications

Gypenoside XIII regulates lipid metabolism in HepG2 hepatocytes and ameliorates nonalcoholic steatohepatitis in mice

Gypenoside XIII regulates lipid metabolism in HepG2 hepatocytes and ameliorates nonalcoholic steatohepatitis in mice

Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis

Molecular Docking Study of Phytosterols in Lygodium microphyllum Towards SIRT1 and AMPK, the in vitro Brine Shrimp Toxicity Test, and the Phenols and Sterols Levels in the Extract

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