Berberine improves hepatic insulin resistance by activating the SIRT1/Opa1 pathway: An in vitro and in vivo study

Abstract Aim: This study explored whether abnormality in the inner mitochondrial membrane fusion protein optic atrophy 1 (Opa1) causes hepatic insulin resistance and whether berberine (BBR) can prevent hepatic insulin resistance through the SIRT1/Opa1 pathway. Method: High-fat diet (HFD)-fed mice and db/db mice were used as animal models to study hepatic insulin resistance in vivo . Insulin resistance, morphological changes, and mitochondrial injury of the liver were examined to explore the effects of BBR. SIRT1/Opa1 protein expressions were determined to confirm whether the signalling pathway was damaged in the model animals and involved in BBR treatment. A palmitate (PA)-induced hepatocyte insulin resistance model was established in HepG2 cells in vitro . Opa1 silencing and SIRT1 overexpression were induced to verify whether Opa1 abnormality causes hepatocyte insulin resistance and whether SIRT1 could improve this dysfunction. BBR treatment and SIRT1 silencing were employed to prove that BBR can prevent hepatic insulin resistance by activating the SIRT1/Opa1 pathway. Results: We found that Opa1 deficiency caused imbalance in mitochondrial fusion/fission and impaired insulin signalling in the HepG2 cells. SIRT1 and BBR overexpression ameliorated PA-induced insulin resistance, increased Opa1, and improved mitochondrial function. SIRT1 silencing could partly reverse the effects of BBR in the HepG2 cells. SIRT1 and Opa1 were downregulated in the animal models. BBR attenuated hepatic insulin resistance and enhanced SIRT1/Opa1 signalling in the the db/db mice. Conclusion: Opa1 silencing-mediated mitochondrial fusion/fission imbalance could lead to hepatocyte insulin resistance. BBR may improve hepatic insulin resistance by regulating the SIRT1/Opa1 pathway, and thus, it may be used to treat type 2 diabetes.

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GPR21 Inhibition Increases Glucose-Uptake in HepG2 Cells

International Journal of Molecular Sciences ◽

10.3390/ijms221910784 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10784

Author(s):

Gemma K. Kinsella ◽

Stefania Cannito ◽

Valentina Bordano ◽

John C. Stephens ◽

Arianna C. Rosa ◽

...

Keyword(s):

Glucose Uptake ◽

Hepg2 Cells ◽

Insulin Signalling ◽

Hepatic Insulin Resistance ◽

In Vivo Studies ◽

Negative Effects ◽

Cellular Models ◽

Insulin Signalling Pathway ◽

Novel Strategy

GPR21 is a constitutively active, orphan, G-protein-coupled receptor, with in vivo studies suggesting its involvement in the modulation of insulin sensitivity. However, its precise contribution is not fully understood. As the liver is both a major target of insulin signalling and critically involved in glucose metabolism, the aim of this study was to examine the role of GPR21 in the regulation of glucose uptake and production in human hepatocytes. In particular, HepG2 cells, which express GPR21, were adopted as cellular models. Compared with untreated cells, a significant increase in glucose uptake was measured in cells treated with siRNA to downregulate GPR21 expression or with the GPR21-inverse agonist, GRA2. Consistently, a significantly higher membrane translocation of GLUT-2 was measured under these conditions. These effects were accompanied by an increased ratio of phAKT(Ser473)/tot-AKT and phGSK-3β(Ser9)/tot-GSK-3β, thus indicating a marked activation of the insulin signalling pathway. Moreover, a significant reduction in ERK activation was observed with GPR21 inhibition. Collectively, these results indicate that GPR21 mediates the negative effects on glucose uptake by the liver cells. In addition, they suggest that the pharmacological inhibition of GPR21 could be a novel strategy to improve glucose homeostasis and counteract hepatic insulin resistance.

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Interleukin-6 Depletion Selectively Improves Hepatic Insulin Action in Obesity

Endocrinology ◽

10.1210/en.2004-1468 ◽

2005 ◽

Vol 146 (8) ◽

pp. 3417-3427 ◽

Cited By ~ 172

Author(s):

Peter J. Klover ◽

Alicia H. Clementi ◽

Robert A. Mooney

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Receptor ◽

Endogenous Glucose Production ◽

Hepatic Insulin Resistance ◽

Stat3 Phosphorylation ◽

Insulin Dependent ◽

Significant Change

Abstract Obesity and insulin resistance are considered chronic inflammatory states, in part because circulating IL-6 is elevated. Exogenous IL-6 can induce hepatic insulin resistance in vitro and in vivo. The importance of endogenous IL-6, however, to insulin resistance of obesity is unresolved. To test the hypothesis that IL-6 contributes to the inflammation and insulin resistance of obesity, IL-6 was depleted in Lepob mice by injection of IL-6-neutralizing antibody. In untreated Lepob mice, signal transducer and activator of transcription-3 (STAT3) activation was increased compared with that in lean controls, consistent with an inflammatory state. With IL-6 depletion, activation of STAT3 in liver and adipose tissue and expression of haptoglobin were reduced. Expression of the IL-6-dependent, hepatic acute phase protein fibrinogen was also decreased. Using the hyperinsulinemic-euglycemic clamp technique, insulin-dependent suppression of endogenous glucose production was 89% in IL-6-depleted Lepob mice, in contrast to only 32% in Lepob controls, indicating a marked increase in hepatic insulin sensitivity. A significant change in glucose uptake in skeletal muscle after IL-6 neutralization was not observed. In a direct comparison of hepatic insulin signaling in Lepob mice treated with anti-IL-6 vs. IgG-treated controls, insulin-dependent insulin receptor autophosphorylation and activation of Akt (pSer473) were increased by nearly 50% with IL-6 depletion. In adipose tissue, insulin receptor signaling showed no significant change despite major reductions in STAT3 phosphorylation and haptoglobin expression. In diet-induced obese mice, depletion of IL-6 improved insulin responsiveness in 2-h insulin tolerance tests. In conclusion, these results indicate that IL-6 plays an important and selective role in hepatic insulin resistance of obesity.

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Mulberry Anthocyanin Extract Ameliorates Oxidative Damage in HepG2 Cells and Prolongs the Lifespan of Caenorhabditis elegans through MAPK and Nrf2 Pathways

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/7956158 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 19

Author(s):

Fujie Yan ◽

Yushu Chen ◽

Ramila Azat ◽

Xiaodong Zheng

Keyword(s):

Oxidative Stress ◽

Caenorhabditis Elegans ◽

Hepg2 Cells ◽

Insulin Signalling ◽

Glucose Consumption ◽

Redox Status ◽

C Elegans ◽

Beneficial Effects

Mulberry anthocyanins possess many pharmacological effects including liver protection, anti-inflammation, and anticancer. The aim of this study was to evaluate whether mulberry anthocyanin extract (MAE) exerts beneficial effects against oxidative stress damage in HepG2 cells and Caenorhabditis elegans. In vitro, MAE prevented cytotoxicity, increased glucose consumption and uptake, and eliminated excessive intracellular free radicals in H2O2-induced cells. Moreover, MAE pretreatment maintained Nrf2, HO-1, and p38 MAPK stimulation and abolished upregulation of p-JNK, FOXO1, and PGC-1α that were involved in oxidative stress and insulin signalling modulation. In vivo, extended lifespan was observed in C. elegans damaged by paraquat in the presence of MAE, while these beneficial effects were disappeared in pmk-1 and daf-16 mutants. PMK-1 and SKN-1 were activated after exposure to paraquat and MAE suppressed PMK-1 activation but enhanced SKN-1 stimulation. Our findings suggested that MAE recovered redox status in HepG2 cells and C. elegans that suffered from oxidative stress, which might be by targeting MAPKs and Nrf2.

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New insight into the mechanisms of ectopic fat deposition improvement after bariatric surgery

Scientific Reports ◽

10.1038/s41598-019-53702-4 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Giulia Angelini ◽

Lidia Castagneto Gissey ◽

Giulia Del Corpo ◽

Carla Giordano ◽

Bruna Cerbelli ◽

...

Keyword(s):

Insulin Resistance ◽

Bariatric Surgery ◽

Insulin Sensitivity ◽

Hepatic Insulin Resistance ◽

Alcoholic Fatty Liver ◽

Fat Accumulation ◽

Impaired Liver ◽

Ectopic Fat Deposition

AbstractNon-alcoholic fatty-liver disease (NAFLD) is frequent in obese patients and represents a major risk factor for the development of diabetes and its complications. Bariatric surgery reverses the hepatic features of NAFLD. However, its mechanism of action remains elusive. We performed a comprehensive analysis of the mechanism leading to the improvement of NAFLD and insulin resistance in both obese rodents and humans following sleeve-gastrectomy (SG). SG improved insulin sensitivity and reduced hepatic and monocyte fat accumulation. Importantly, fat accumulation in monocytes was well comparable to that in hepatocytes, suggesting that Plin2 levels in monocytes might be a non-invasive marker for the diagnosis of NAFLD. Both in vitro and in vivo studies demonstrated an effective metabolic regeneration of liver function and insulin sensitivity. Specifically, SG improved NAFLD significantly by enhancing AMP-activated protein kinase (AMPK) phosphorylation and chaperone-mediated autophagy (CMA) that translate into the removal of Plin2 coating lipid droplets. This led to an increase in lipolysis and specific amelioration of hepatic insulin resistance. Elucidating the mechanism of impaired liver metabolism in obese subjects will help to design new strategies for the prevention and treatment of NAFLD.

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Psoralea corylifolia L. Seed Extract Attenuates Methylglyoxal-Induced Insulin Resistance by Inhibition of Advanced Glycation End Product Formation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/4310319 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Cao-Sang Truong ◽

Eunhui Seo ◽

Hee-Sook Jun

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Hepg2 Cells ◽

Product Formation ◽

The Body ◽

Psoralea Corylifolia ◽

Advanced Glycation ◽

Metabolic Conditions

Accumulation of advanced glycation end products (AGEs) in the body has been implicated in the pathogenesis of metabolic conditions, such as diabetes mellitus. Methylglyoxal (MGO), a major precursor of AGEs, has been reported to induce insulin resistance in both in vitro and in vivo studies. Psoralea corylifolia seeds (PCS) have been used as a traditional medicine for several diseases, but their potential application in treating insulin resistance has not yet been evaluated. This study is aimed at investigating whether PCS extract could attenuate insulin resistance induced by MGO. Male C57BL/6N mice (6 weeks old) were administered 1% MGO in their drinking water for 18 weeks, and the PCS extract (200 or 500 mg/kg) was orally administered daily from the first day of the MGO administration. We observed that both 200 and 500 mg/kg PCS extract treatment significantly improved glucose tolerance and insulin sensitivity and markedly restored p-Akt and p-IRS1/2 expression in the livers of the MGO-administered mice. Additionally, the PCS extract significantly increased the phosphorylation of Akt and IRS-1/2 and glucose uptake in MGO-treated HepG2 cells. Further studies showed that the PCS extract inhibited MGO-induced AGE formation in the HepG2 cells and in the sera of MGO-administered mice. PCS extract also increased the expression of glyoxalase 1 (GLO1) in the liver tissue of MGO-administered mice. The PCS extract significantly decreased the phosphorylation of ERK, p38, and NF-κB and suppressed the mRNA expression of proinflammatory molecules including TNF-α and IL-1β and iNOS in MGO-administered mice. Additionally, we demonstrated that the PCS extract attenuated oxidative stress, as evidenced by the reduced ROS production in the MGO-treated cells and the enhanced expression of antioxidant enzymes in the liver of MGO-administered mice. Thus, PCS extract ameliorated the MGO-induced insulin resistance in HepG2 cells and in mice by reducing oxidative stress via the inhibition of AGE formation. These findings suggest the potential of PCS extract as a candidate for the prevention and treatment of insulin resistance.

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Erchen Decoction and Linguizhugan Decoction Ameliorate Hepatic Insulin Resistance by Inhibiting IRS-1Ser307 Phosphorylation In Vivo and In Vitro

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/1589871 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Huicun Zhang ◽

Na Ta ◽

Pengmin Chen ◽

Hongbing Wang

Keyword(s):

Insulin Resistance ◽

Histopathological Examination ◽

Hepatic Insulin Resistance ◽

Hepatocyte Proliferation ◽

Therapeutic Effects ◽

Protective Effects ◽

Serum Aminotransferase ◽

Nonalcoholic Fatty Liver

Erchen decoction (ECD) and Linguizhugan decoction (LGZGD), both are Chinese herbal formula, have been used clinically for the treatment of nonalcoholic fatty liver disease (NAFLD). However, their therapeutic mechanisms are still unclear. Because insulin resistance (IR) is a key etiological factor in the pathology of high-fat diet- (HFD-) induced NAFLD, in this study, the protective effects of ECD and LGZGD on HFD-induced insulin resistance in rats were evaluated and their mechanisms were investigated by OGTT and Western blot. The results showed that treatment with ECD and LGZGD significantly improved insulin resistance and liver damage in rats, evidenced by supported serum aminotransferase levels and the histopathological examination. ECD and LGZGD also showed significant protective effects against HFD-induced hyperlipidemia and the inhibition of the hepatocyte proliferation by palmitate. Furthermore, supplementation of ECD and LGZGD decreased TNF-α, NF-κB, and IRS-1Ser307 phosphorylation expressions in vivo and in vitro. These results indicated that ECD and LGZGD have protective effects against HFD-induced liver IR and their underlying mechanisms involve the TNF-αand insulin pathway. These findings would be beneficial for understanding of the therapeutic effects of ECD and LGZGD in treatment of NAFLD.

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Sulforaphane Prevents Hepatic Insulin Resistance by Blocking Serine Palmitoyltransferase 3-Mediated Ceramide Biosynthesis

Nutrients ◽

10.3390/nu11051185 ◽

2019 ◽

Vol 11 (5) ◽

pp. 1185 ◽

Cited By ~ 10

Author(s):

Wendi Teng ◽

Yuan Li ◽

Min Du ◽

Xingen Lei ◽

Siyu Xie ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Signaling Pathway ◽

Glucose Homeostasis ◽

Hepg2 Cells ◽

Hepatic Insulin Resistance ◽

Serine Palmitoyltransferase ◽

Insulin Resistant ◽

Ceramide Production

Sulforaphane (SFA), a naturally active isothiocyanate compound from cruciferous vegetables used in clinical trials for cancer treatment, was found to possess potency to alleviate insulin resistance. But its underlying molecular mechanisms are still incompletely understood. In this study, we assessed whether SFA could improve insulin sensitivity and glucose homeostasis both in vitro and in vivo by regulating ceramide production. The effects of SFA on glucose metabolism and expression levels of key proteins in the hepatic insulin signaling pathway were evaluated in insulin-resistant human hepatic carcinoma HepG2 cells. The results showed that SFA dose-dependently increased glucose uptake and intracellular glycogen content by regulating the insulin receptor substrate 1 (IRS-1)/protein kinase B (Akt) signaling pathway in insulin-resistant HepG2 cells. SFA also reduced ceramide contents and downregulated transcription of ceramide-related genes. In addition, knockdown of serine palmitoyltransferase 3 (SPTLC3) in HepG2 cells prevented ceramide accumulation and alleviated insulin resistance. Moreover, SFA treatment improved glucose tolerance and insulin sensitivity, inhibited SPTLC3 expression and hepatic ceramide production and reduced hepatic triglyceride content in vivo. We conclude that SFA recovers glucose homeostasis and improves insulin sensitivity by blocking ceramide biosynthesis through modulating SPTLC3, indicating that SFA may be a potential candidate for prevention and amelioration of hepatic insulin resistance via a ceramide-dependent mechanism.

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Apple polyphenol extract improves insulin sensitivity in vitro and in vivo in animal models of insulin resistance

Nutrition & Metabolism ◽

10.1186/s12986-016-0088-8 ◽

2016 ◽

Vol 13 (1) ◽

Cited By ~ 15

Author(s):

Manuel Manzano ◽

María D Giron ◽

José D. Vilchez ◽

Natalia Sevillano ◽

Nuri El-Azem ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Animal Models

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Leptin as a Potential Regulator of FGF21

Cellular Physiology and Biochemistry ◽

10.1159/000443070 ◽

2016 ◽

Vol 38 (3) ◽

pp. 1218-1225 ◽

Cited By ~ 10

Author(s):

Mohamed Asrih ◽

Christelle Veyrat-Durebex ◽

Anne-Laure Poher ◽

Jacqueline Lyautey ◽

Françoise Rohner-Jeanrenaud ◽

...

Keyword(s):

Insulin Resistance ◽

Hepg2 Cells ◽

Wistar Rats ◽

Metabolic Diseases ◽

Fibroblast Growth Factor 21 ◽

New Findings ◽

Expression Site ◽

Fgf21 Expression

Background/Aims: Fibroblast growth factor 21 (FGF21), a potent metabolic regulator, has been shown to improve insulin sensitivity in animal models of insulin resistance. Several studies have focused on identifying mediators of FGF21 effects. However, the identification of factors involved in FGF21 regulation is far from complete. As leptin is a potent metabolic modulator as well, we aimed at characterizing whether leptin may regulate FGF21. Methods: We investigated a potential regulation of FGF21 by leptin in vivo in Wistar rats and in vitro using human derived hepatocarcinoma HepG2 cells. This model was chosen as the liver is considered the main FGF21 expression site. Results: We found that leptin injections increased plasma FGF21 levels in adult Wistar rats. This was confirmed in vitro, as leptin increased FGF21 expression in HepG2 cells. We also showed that the leptin effect on FGF21 expression was mediated by STAT3 activation in HepG2 cells. Conclusion: New findings regarding a leptin-STAT3-FGF21 axis were provided in this study, although investigating the exact mechanisms linking leptin and FGF21 are still needed. These results are of great interest in the context of identifying potential new clinical approaches to treat metabolic diseases associated with insulin resistance, such as obesity and type 2 diabetes.

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