Metformin maintains intrahepatic triglyceride content through increased hepatic de novo lipogenesis

Green, Charlotte; Marjot, Thomas; Walsby-Tickle, John; Charlton, Catriona; Cornfield, Thomas; Westcott, Felix; Pinnick, Katherine E.; Moolla, Ahmad; Hazlehurst, Jonathan; McCullagh, James; Tomlinson, Jeremy; Hodson, Leanne

doi:10.1530/eje-21-0850

Cited by 18 publications

(14 citation statements)

References 48 publications

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“…These findings were in accordance with earlier studies suggesting a beneficial lipid-lowering effect of metformin (Song et al, 2015;Choi et al, 2017;Zhu et al, 2018). In contrast, a recent report showed that metformin treatment improved weight loss and insulin resistance in humans without improvement in intrahepatic TG content, partly through increased hepatic fatty acids (FA) synthesis (Green et al, 2022). The discrepancy in findings with our results may due to dose and duration of metformin exposure or differential experimental condition such as diet structure.…”

Section: Discussionsupporting

confidence: 91%

X-box binding protein 1: A new metabolic mediator and drug target of metformin?

et al. 2022

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Accumulating evidence has demonstrated that metformin improved hypertriglyceridemia. The present study aim to investigate the molecular mechanism by which metformin improves hypertriglyceridemia via regulation of diacylglycerol O-acyltransferase 2 (DGAT2) and X-box binding protein 1 (XBP1) in the liver and whether AMP-activated protein kinase (AMPK) is involved. Mice were fed a high-fat diet (HFD) or high-fat diet with metformin for 5 weeks to evaluate the effect of metformin on triglyceride (TG) levels and expression of DGAT2 and XBP1 in the liver. In vitro HepG2 cells or XBP1 knockout AML12 hepatocytes were stimulated with metformin, palmitic acid or small interfering RNA inducing XBP1 knockdown, or dominant-negative mutant AMPK plasmid. Metformin treatment reduced hepatic TG levels in the liver of HFD-fed mice. Expression of nuclear and cytoplasmic XBP1 protein and its downstream target gene DGAT2 decreased in the liver of HFD-fed mice and HepG2 cells after metformin treatment. AMPK inactivation or overexpression of XBP1 attenuates this effect. Our preliminary results demonstrate that metformin activates AMPK to reduce TG synthesis by inhibiting the XBP1-mediated DGAT2 pathway, at least in part, suggesting that XBP1 is a new metabolic mediator for metformin treatment of hypertriglyceridemia and associated metabolic disease.

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Section: Discussionsupporting

confidence: 91%

X-box binding protein 1: A new metabolic mediator and drug target of metformin?

et al. 2022

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“…Metformin also has a beneficial effect on the lipid profiles of patients with NAFLD, according to a previous trial, where 500 mg metformin administered for 4 months significantly decreased liver enzyme and triglyceride levels, and increased high-density lipoprotein (HDL)-cholesterol levels in patients (68). This is in line with another study which revealed that 500 mg metformin administered for 3 months decreased VLDL and triglyceride levels in 10 patients who were at a risk of developing NAFLD (69). Another study similarly reported that the daily administration of 850 mg metformin for 6 months reduced liver enzyme, total cholesterol and triglyceride levels, and increased HDL-cholesterol levels (70).…”

Section: Nafld For 6 Monthssupporting

confidence: 75%

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

et al. 2022

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Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent ailment worldwide. Moreover, de novo lipogenesis (DNL) is considered a critical factor in the development of NAFLD; hence, its inhibition is a promising target for the prevention of fatty liver disease. There is evidence to indicate that AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) may play a crucial role in DNL and are the regulatory proteins in type 2 diabetes mellitus, obesity and cardiovascular disease. Therefore, AMPK and SIRT1 may be promising targets for the treatment of NAFLD. The present review article thus aimed to summarize the findings of clinical studies published during the past decade that suggested the beneficial effects of AMPK and SIRT1, using their specific activators and their combined effects on fatty liver disease. Contents1. Introduction 2. Data collection methods 3. De novo lipogenesis 4. AMPK 5. SIRT1 6. AMPK activators in NAFLD clinical studies 7. The SIRT1 activator, resveratrol, in NAFLD clinical studies 8. The combination of AMPK and SIRT1 activation 9. Conclusion

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“…As such, the effect of metformin administered in this model, with a hypercaloric diet, had not been explored. Despite the controversial effect of metformin in in vivo studies, some human studies suggested that metformin maintains the intrahepatic TG content [ 25 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Combining Dietary Intervention with Metformin Treatment Enhances Non-Alcoholic Steatohepatitis Remission in Mice Fed a High-Fat High-Sucrose Diet

et al. 2022

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Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are serious health concerns for which lifestyle interventions are the only effective first-line treatment. Dietary interventions are effective in body weight reduction, but not in improving insulin sensitivity and hepatic lipid mobilization. Conversely, metformin increases insulin sensitivity and promotes the inhibition of de novo hepatic lipogenesis. In this study, we evaluated the metformin effectiveness in NASH prevention and treatment, when combined with dietary intervention in male mice fed a high-fat high-sucrose diet (HFHSD). Eighty 5-week-old C57BL/6J male mice were fed a chow or HFHSD diet and sacrificed at 20 or 40 weeks. The HFHSD-fed mice developed NASH after 20 weeks. Lipoprotein and lipidomic analyses showed that the changes associated with diet were not prevented by metformin administration. HFHSD-fed mice subject to dietary intervention combined with metformin showed a 19.6% body weight reduction compared to 9.8% in those mice subjected to dietary intervention alone. Lower hepatic steatosis scores were induced. We conclude that metformin should not be considered a preventive option for NAFLD, but it is effective in the treatment of this disorder when combined with dietary intervention.

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Metformin maintains intrahepatic triglyceride content through increased hepatic de novo lipogenesis

Cited by 18 publications

References 48 publications

X-box binding protein 1: A new metabolic mediator and drug target of metformin?

X-box binding protein 1: A new metabolic mediator and drug target of metformin?

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

Combining Dietary Intervention with Metformin Treatment Enhances Non-Alcoholic Steatohepatitis Remission in Mice Fed a High-Fat High-Sucrose Diet

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