Liver-Specific Activation of AMPK Prevents Steatosis on a High-Fructose Diet

Woods, Angela; Williams, J; Muckett, Phillip; Mayer, Faith V.; Liljevald, Maria; Bohlooly‐Y, Mohammad; Carling, David

doi:10.1016/j.celrep.2017.03.011

Cited by 167 publications

(173 citation statements)

References 42 publications

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“…The first pathway to be identified was the inhibition of lipid and sterol synthesis by AMPK through inhibitory phosphorylation of the acetyl-CoA carboxylases ACC1 and ACC2, which catalyse the first step in de novo lipid synthesis, and inhibitory phosphorylation of HMG-CoA reductase (HMGCR), which catalyses the rate-limiting step in cholesterol synthesis 6,7 . This function of AMPK has major implications for the use of direct activators in the treatment of diseases associated with excess fatty acid production, such as nonalcoholic fatty liver disease (NAFLD) 85 , and is consistent with the lipid-lowering effects seen upon liver-specific expression of activated AMPK 86 . AMPK also prevents the storage of glycogen by inhibitory phosphorylation of the glycogen synthases GYS1 and GYS2 (REF.…”

Section: Regulation Of Metabolism By Ampkmentioning

confidence: 59%

AMPK: guardian of metabolism and mitochondrial homeostasis

Herzig

Shaw

2017

Nat Rev Mol Cell Biol

2,319

1,706

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Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy This Review discusses how AMPK functions as a central mediator of the cellular response to energetic stress and mitochondrial insults and coordinates multiple features of autophagy and mitochondrial biology.

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Section: Regulation Of Metabolism By Ampkmentioning

confidence: 59%

AMPK: guardian of metabolism and mitochondrial homeostasis

Herzig

Shaw

2017

Nat Rev Mol Cell Biol

2,319

1,706

View full text Add to dashboard Cite

show abstract

“…Recently, Woods et al reported that mice expressing a constitutively active form of AMPK (γ1‐Asp316Ala) in the liver were protected from developing hepatic steatosis on a high‐fructose diet. These mice had essentially the reciprocal phenotype to the HMGCR KI mice that develop steatosis on a high‐carbohydrate diet.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Adenosine Monophosphate–Activated Protein Kinase–3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Signaling Leads to Hypercholesterolemia and Promotes Hepatic Steatosis and Insulin Resistance

et al. 2018

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Adenosine monophosphate–activated protein kinase (AMPK) regulates multiple signaling pathways involved in glucose and lipid metabolism in response to changes in hormonal and nutrient status. Cell culture studies have shown that AMPK phosphorylation and inhibition of the rate‐limiting enzyme in the mevalonate pathway 3‐hydroxy‐3‐methylglutaryl (HMG) coenzyme A (CoA) reductase (HMGCR) at serine‐871 (Ser871; human HMGCR Ser872) suppresses cholesterol synthesis. In order to evaluate the role of AMPK‐HMGCR signaling in vivo, we generated mice with a Ser871‐alanine (Ala) knock‐in mutation (HMGCR KI). Cholesterol synthesis was significantly suppressed in wild‐type (WT) but not in HMGCR KI hepatocytes in response to AMPK activators. Liver cholesterol synthesis and cholesterol levels were significantly up‐regulated in HMGCR KI mice. When fed a high‐carbohydrate diet, HMGCR KI mice had enhanced triglyceride synthesis and liver steatosis, resulting in impaired glucose homeostasis. Conclusion: AMPK‐HMGCR signaling alone is sufficient to regulate both cholesterol and triglyceride synthesis under conditions of a high‐carbohydrate diet. Our findings highlight the tight coupling between the mevalonate and fatty acid synthesis pathways as well as revealing a role of AMPK in suppressing the deleterious effects of a high‐carbohydrate diet.

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“…Activation of AMPK in the liver confers protection against the accumulation of triglycerides and inhibits de novo lipogenesis without influencing fatty acid oxidation (Woods et al. ). Curcumin activates AMPK and thus protects the liver from developing steatosis (Jiménez‐Flores et al.…”

Section: Discussionmentioning

confidence: 99%

The long‐term protective effects of neonatal administration of curcumin against nonalcoholic steatohepatitis in high‐fructose‐fed adolescent rats

et al. 2019

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There is an increased prevalence of nonalcoholic steatohepatitis ( NASH ) in adolescents. The suckling period is developmentally plastic, affecting later health outcomes. We investigated whether neonatal administration of curcumin would provide protection against the development of NASH later in adolescence in rats fed a high‐fructose diet. From postnatal day ( PN ) 6 to PN 21, the pups ( N = 128) were allocated to four groups and orally gavaged daily with either 0.5% dimethyl sulfoxide solution (vehicle control), curcumin (500 mg·kg −1 ), fructose (20%, w/v) or curcumin and fructose combined. All the pups were weaned and half the rats in each group had tap water, whereas the other received fructose (20%) as their drinking fluid ad libitum for 6 weeks. The rats’ liver NASH scores, lipid content, and RNA gene expression ratios of AMPK α and TNF α were determined. Hepatic lipid content was similar across the treatment groups in the males ( P > 0.05, ANOVA ). In the females, the hepatic lipid content in the treatment groups ranged from 2.7 to 4.3%. The livers of male and female rats that had fructose either as neonates and/or postweaning had significantly marked inflammation ( P = 0.0112, Kruskal–Wallis) and fibrosis ( P < 0.0001, ANOVA ) which were attenuated by curcumin. The hepatic gene expression ratios for AMPK α in both sexes were significantly downregulated ( P < 0.0001, ANOVA ), whereas the expression ratios of TNF α were significantly upregulated ( P < 0.0001) in rats fed a high‐fructose diet pre and/or postweaning compared to the other groups. Neonatal curcumin administration is a potential natural pharmacological candidate for the prevention of NASH .

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Liver-Specific Activation of AMPK Prevents Steatosis on a High-Fructose Diet

Cited by 167 publications

References 42 publications

AMPK: guardian of metabolism and mitochondrial homeostasis

AMPK: guardian of metabolism and mitochondrial homeostasis

Inhibition of Adenosine Monophosphate–Activated Protein Kinase–3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Signaling Leads to Hypercholesterolemia and Promotes Hepatic Steatosis and Insulin Resistance

The long‐term protective effects of neonatal administration of curcumin against nonalcoholic steatohepatitis in high‐fructose‐fed adolescent rats

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