Phosphorylation of Acetyl-CoA Carboxylase by AMPK Reduces Renal Fibrosis and Is Essential for the Anti-Fibrotic Effect of Metformin

Lee, Mardiana; Katerelos, Marina; Gleich, Kurt; Galić, Sandra; Kemp, Bruce E.; Mount, Peter F.; Power, David A.

doi:10.1681/asn.2018010050

Cited by 100 publications

(84 citation statements)

References 41 publications

(51 reference statements)

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“…These effects may be mediated by the AMPK signaling pathway, which can regulate cell growth and energy utilization. Another study found that in a CKD mouse model, metformin could suppress kidney injury and improve kidney function, through AMPK-mediated ACC signaling (113). In humans, metformin is also beneficial to kidney diseases.…”

Section: Metformin and Renal Diseasesmentioning

confidence: 98%

Metformin and Its Benefits for Various Diseases

2020

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Metformin is a widely used biguanide drug due to its safety and low cost. It has been used for over 60 years to treat type 2 diabetes at the early stages because of its outstanding ability to decrease plasma glucose levels. Over time, different uses of metformin were discovered, and the benefits of metformin for various diseases and even aging were verified. These diseases include cancers (e.g., breast cancer, endometrial cancer, bone cancer, colorectal cancer, and melanoma), obesity, liver diseases, cardiovascular disease, and renal diseases. Metformin exerts different effects through different signaling pathways. However, the underlying mechanisms of these different benefits remain to be elucidated. The aim of this review is to provide a brief summary of the benefits of metformin and to discuss the possible underlying mechanisms.

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Section: Metformin and Renal Diseasesmentioning

confidence: 98%

Metformin and Its Benefits for Various Diseases

2020

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“…Chronic hypertension, obesity and type 2 diabetes accelerate the progression of chronic kidney disease and autosomal dominant polycystic kidney disease towards end-stage renal disease. Metformin-induced activation of AMPK improves renal function, an effect that has recently been linked to reductions in fibrosis and the phosphorylation of ACC 310 . Recent studies have also examined the effects of a direct pharmacological AMPK β1 activator in a mouse model of diabetes and hypertension and found marked reductions in proteinuria, improvements in kidney histology and reductions in S6 phosphorylation, suggesting that activation of AMPK may reduce the development of dia-betic nephropathy by suppressing mTOR 27 .…”

Section: ) (Table 1)mentioning

confidence: 99%

AMP-activated protein kinase: the current landscape for drug development

Steinberg

Carling

2019

Nat Rev Drug Discov

443

375

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Since the discovery of AMP-activated protein kinase (AMPK) as a central regulator of energy homeostasis, many exciting insights into its structure, regulation and physiological roles have been revealed. While exercise, caloric restriction, metformin and many natural products increase AMPK activity and exert a multitude of health benefits, developing direct activators of AMPK to elucidate the role of AMPK in these beneficial effects has been challenging. However, in recent years, direct AMPK activators have been identified and tested in preclinical models, and a small number have entered clinical trials. Despite these advances, which disease(s) represent the best indications for therapeutic AMPK activation and the long-term safety of such approaches remain to be established. Commented [WS2]: Au: "The optimal consensus motif of AMPK substrates has been established (BOX 3)" OK?

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“…AMPK is a major controller of fatty acid metabolism. It inhibits acetyl-CoA carboxylase by phosphorylation ACC1 at Ser79 and ACC2 at Ser212 [243]. Additionally, malonyl-CoA inhibits CPT1 found in mitochondrial membrane to facilitate fatty acid entry into mitochondria associated with increased FAO [244].…”

Section: Role Of Ampk In Promoting Cancer Cell Oxidative Metabolismmentioning

confidence: 99%

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

Moldogazieva

Mokhosoev

Terentiev

2020

Cancers

103

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It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over recent years has increasingly provided evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism, even in the same tumor. This phenomenon, denoted as cancer cell metabolic plasticity or hybrid metabolism, depends on a tumor micro-environment that is highly heterogeneous and influenced by an intensity of vasculature and blood flow, oxygen concentration, and nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, and reactive oxygen species (ROS), among others. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of a switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, glucose transporters (GLUTs), and AMPK with other regulatory proteins including oncogenes such as c-Myc, p53, and KRAS; growth factor-initiated protein kinase B (PKB)/Akt, phosphatidyl-3-kinase (PI3K), and mTOR signaling pathways; and tumor suppressors such as liver kinase B1 (LKB1) and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discover novel anti-cancer drugs.

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Phosphorylation of Acetyl-CoA Carboxylase by AMPK Reduces Renal Fibrosis and Is Essential for the Anti-Fibrotic Effect of Metformin

Abstract: These data indicate that reduced phosphorylation of ACC after renal injury contributes to the development of TIF, and that phosphorylation of ACC is required for metformin's antifibrotic action in the kidney.

Cited by 100 publications

References 41 publications

Metformin and Its Benefits for Various Diseases

Metformin and Its Benefits for Various Diseases

AMP-activated protein kinase: the current landscape for drug development

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

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