Treatment of nonalcoholic fatty liver disease: role of AMPK

Smith, Brennan K.; Marcinko, Katarina; Desjardins, Eric M.; Lally, James; Ford, Rebecca J.; Steinberg, Gregory R.

doi:10.1152/ajpendo.00225.2016

Cited by 386 publications

(358 citation statements)

References 139 publications

(110 reference statements)

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“…As metabolic improvements upon FGF21 administration are associated with reduced expression of ACC1 and ACC2 in liver [27], we used previously described knock-in mutation mice (ACC DKI) to test whether AMPK's inhibitory phosphorylation of ACC (ACC1-S79 and ACC2-S212) mediated the metabolic benefits of FGF21 administration. When ACC is phosphorylated by AMPK, as occurs with metformin treatment, malonyl-CoA levels are reduced, leading to the suppression of de novo lipogenesis and the reduction of hepatic lipid content and insulin resistance [31], [42]. However, we observed no differences between wildtype and ACC DKI mice in response to FGF21 administration over two weeks.…”

Section: Discussionmentioning

confidence: 50%

FGF21 does not require adipocyte AMP-activated protein kinase (AMPK) or the phosphorylation of acetyl-CoA carboxylase (ACC) to mediate improvements in whole-body glucose homeostasis

Mottillo

Desjardins

Fritzen

et al. 2017

Molecular Metabolism

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ObjectiveFibroblast growth factor 21 (FGF21) shows great potential for the treatment of obesity and type 2 diabetes, as its long-acting analogue reduces body weight and improves lipid profiles of participants in clinical studies; however, the intracellular mechanisms mediating these effects are poorly understood. AMP-activated protein kinase (AMPK) is an important energy sensor of the cell and a molecular target for anti-diabetic medications. This work examined the role of AMPK in mediating the glucose and lipid-lowering effects of FGF21.MethodsInducible adipocyte AMPK β1β2 knockout mice (iβ1β2AKO) and littermate controls were fed a high fat diet (HFD) and treated with native FGF21 or saline for two weeks. Additionally, HFD-fed mice with knock-in mutations on the AMPK phosphorylation sites of acetyl-CoA carboxylase (ACC)1 and ACC2 (DKI mice) along with wild-type (WT) controls received long-acting FGF21 for two weeks.ResultsConsistent with previous studies, FGF21 treatment significantly reduced body weight, adiposity, and liver lipids in HFD fed mice. To add, FGF21 improved circulating lipids, glycemic control, and insulin sensitivity. These effects were independent of adipocyte AMPK and were not associated with changes in browning of white (WAT) and brown adipose tissue (BAT). Lastly, we assessed whether FGF21 exerted its effects through the AMPK/ACC axis, which is critical in the therapeutic benefits of the anti-diabetic medication metformin. ACC DKI mice had improved glucose and insulin tolerance and a reduction in body weight, body fat and hepatic steatosis similar to WT mice in response to FGF21 administration.ConclusionsThese data illustrate that the metabolic improvements upon FGF21 administration are independent of adipocyte AMPK, and do not require the inhibitory action of AMPK on ACC. This is in contrast to the anti-diabetic medication metformin and suggests that the treatment of obesity and diabetes with the combination of FGF21 and AMPK activators merits consideration.

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Section: Discussionmentioning

confidence: 50%

FGF21 does not require adipocyte AMP-activated protein kinase (AMPK) or the phosphorylation of acetyl-CoA carboxylase (ACC) to mediate improvements in whole-body glucose homeostasis

Mottillo

Desjardins

Fritzen

et al. 2017

Molecular Metabolism

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“…Resulting lipid droplets are formed from triglyceride (TG) [25][26][27]. AMPK is a master regulator of both lipid and carbohydrate metabolism in liver [15]. In our study, its function was inhibited by HFD and AMPK became unable to maintain energy balance by itself and by signaling other important targets such as PPAR-α and FoxO1 (Fig.…”

Section: Discussionmentioning

confidence: 81%

Bioactive Peptide Improves Diet-Induced Hepatic Fat Deposition and Hepatocyte Proinflammatory Response in SAMP8 Ageing Mice

DUmeUS¹,

Shibu²,

Lin³

et al. 2018

Cell Physiol Biochem

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Background/Aims: High-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) poses therapeutic challenges in elderly subjects. Due to lack of efficient drug therapy, plant-based bioactive peptides have been studied as alternative strategy in NAFLD and for less toxicity in elderly. To mimic fatty liver in aging conditions, researchers highly commended the genetically engineered strains SAMP8 (senescence-accelerated mice prone 8). However, there is a paucity of reports about the anti-steatosis effects of bioactive peptides against fatty liver development under a combined action of high-fat diet exposure and aging process. This study was conducted to evaluate the activity of DIKTNKPVIF peptide synthesized from alcalase-generated potato protein hydrolysate (PH), on reducing HFD-driven and steatosis-associated proinflammatory reaction in ageing model. Methods: Five groups of six-month-old SAMP8 mice (n=4, each) were fed either a normal chow (NC group) for 14 weeks upon sacrifice, or induced with a 6-week HFD feeding, then treated without (HCO group) or with an 8-week simultaneous administration of peptide (HPEP group), protein (HPH group) or probucol (HRX group). Liver organs were harvested from each group for histological analysis and immunoblot assay. Results: In contrast to NC, extensive fat accumulation was visualized in the liver slides of HCO. Following the trends of orally administered PH, intraperitoneally injected peptide reduces hepatic fat deposition and causes at protein level, a significant decrease in HFD-induced proinflammatory mediators p-p38 MAPK, FGF-2, TNF-α, IL-6 with concomitant reactivation of AMPK. However, p-Foxo1 and PPAR-α levels were slightly changed. Conclusion: Oral supplementation of PH and intraperitoneal injection of derived bioactive peptide alleviate proinflammatory reaction associated with hepatosteatosis development in elderly subjects, through activation of AMPK.

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“…Insulin-sensitizing drugs, such as metformin, may correct some of these metabolic disorders [70]. Additionally, the cardiovascular protective effect of metformin in patients with diabetes cannot be attributed only to reduced blood glucose but may also be correlated with the protective role of metformin in lipid metabolism and vascular endothelial function [11, 71]. Studies also suggest that the use of metformin by obese patients with or without diabetes can significantly reduce systemic and visceral fat [72, 73].…”

Section: Discussionmentioning

confidence: 99%

Metformin-Induced Changes of the Coding Transcriptome and Non-Coding RNAs in the Livers of Non-Alcoholic Fatty Liver Disease Mice

Guo

Zhou

Cheng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Recent studies have suggested that changes in non-coding mRNA play a key role in the progression of non-alcoholic fatty liver disease (NAFLD). Metformin is now recommended and effective for the treatment of NAFLD. We hope the current analyses of the non-coding mRNA transcriptome will provide a better presentation of the potential roles of mRNAs and long non-coding RNAs (lncRNAs) that underlie NAFLD and metformin intervention. Methods: The present study mainly analysed changes in the coding transcriptome and non-coding RNAs after the application of a five-week metformin intervention. Liver samples from three groups of mice were harvested for transcriptome profiling, which covered mRNA, lncRNA, microRNA (miRNA) and circular RNA (circRNA), using a microarray technique. Results: A systematic alleviation of high-fat diet (HFD)-induced transcriptome alterations by metformin was observed. The metformin treatment largely reversed the correlations with diabetes-related pathways. Our analysis also suggested interaction networks between differentially expressed lncRNAs and known hepatic disease genes and interactions between circRNA and their disease-related miRNA partners. Eight HFD-responsive lncRNAs and three metformin-responsive lncRNAs were noted due to their widespread associations with disease genes. Moreover, seven miRNAs that interacted with multiple differentially expressed circRNAs were highlighted because they were likely to be associated with metabolic or liver diseases. Conclusions: The present study identified novel changes in the coding transcriptome and non-coding RNAs in the livers of NAFLD mice after metformin treatment that might shed light on the underlying mechanism by which metformin impedes the progression of NAFLD.

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Treatment of nonalcoholic fatty liver disease: role of AMPK

Cited by 386 publications

References 139 publications

FGF21 does not require adipocyte AMP-activated protein kinase (AMPK) or the phosphorylation of acetyl-CoA carboxylase (ACC) to mediate improvements in whole-body glucose homeostasis

FGF21 does not require adipocyte AMP-activated protein kinase (AMPK) or the phosphorylation of acetyl-CoA carboxylase (ACC) to mediate improvements in whole-body glucose homeostasis

Bioactive Peptide Improves Diet-Induced Hepatic Fat Deposition and Hepatocyte Proinflammatory Response in SAMP8 Ageing Mice

Metformin-Induced Changes of the Coding Transcriptome and Non-Coding RNAs in the Livers of Non-Alcoholic Fatty Liver Disease Mice

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