Hepatitis C virus core protein induces hepatic metabolism disorders through down-regulation of the SIRT1–AMPK signaling pathway

Yu, Jing; Sun, Lijie; Liu, Wei; Zhao, Yuwu; Peng, Kang; Yan, Bin

doi:10.1016/j.ijid.2013.01.027

Cited by 51 publications

(48 citation statements)

References 23 publications

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“…The modulation of AMPK has been studied during the infection with other viruses such as hepatitis C virus (HCV), where it was observed the inhibition of this kinase and the concomitant intracellular lipids accumulation [52–54]. As well, the latent membrane protein 1 from Epstein-Bar virus (EBV) inhibits the AMPK activity and the subsequent downstream effectors activation [55].…”

Section: Discussionmentioning

confidence: 99%

DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target

Soto-Acosta¹,

et al. 2017

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Dengue is the most common mosquito-borne viral disease in humans. Changes of lipid-related metabolites in endoplasmic reticulum of dengue virus (DENV) infected cells have been associated with replicative complexes formation. Previously, we reported that DENV infection inhibits HMGCR phosphorylation generating a cholesterol-enriched cellular environment in order to favor viral replication. In this work, using enzymatic assays, ELISA, and WB we found a significant higher activity of HMGCR in DENV infected cells, associated with the inactivation of AMPK. AMPK activation by metformin declined the HMGCR activity suggesting that AMPK inactivation mediates the enhanced activity of HMGCR. A reduction on AMPK phosphorylation activity was observed in DENV infected cells at 12 and 24 hpi. HMGCR and cholesterol co-localized with viral proteins NS3, NS4A and E, suggesting a role for HMGCR and AMPK activity in the formation of DENV replicative complexes. Furthermore, metformin and lovastatin (HMGCR inhibitor) altered this co-localization as well as replicative complexes formation supporting that active HMGCR is required for replicative complexes formation. In agreement, metformin prompted a significant dose-dependent antiviral effect in DENV infected cells, while compound C (AMPK inhibitor) augmented the viral genome copies and the percentage of infected cells. The PP2A activity, the main modulating phosphatase of HMGCR, was not affected by DENV infection. These data demonstrate that the elevated activity of HMGCR observed in DENV infected cells is mediated through AMPK inhibition and not by increase in PP2A activity. Interestingly, the inhibition of this phosphatase showed an antiviral effect in an HMGCR-independent manner. These results suggest that DENV infection increases HMGCR activity through AMPK inactivation leading to higher cholesterol levels in endoplasmic reticulum necessary for replicative complexes formation. This work provides new information about the mechanisms involved in host lipid metabolism during DENV replicative cycle and identifies new potential antiviral targets for DENV replication.

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Section: Discussionmentioning

confidence: 99%

DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target

Soto-Acosta¹,

et al. 2017

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“…As a result, lipid droplets become inaccessible for cell lipases. In addition, CP regulates the expression of protein factors of lipid metabolism [276–279]. Integral action of CP increases the number of lipid droplets and induces their fusion yielding lipid vacuoles [274].…”

Section: Viral Infectionsmentioning

confidence: 99%

Cytoplasmic vacuolization in cell death and survival

et al. 2016

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Cytoplasmic vacuolization (also called cytoplasmic vacuolation) is a well-known morphological phenomenon observed in mammalian cells after exposure to bacterial or viral pathogens as well as to various natural and artificial low-molecular-weight compounds. Vacuolization often accompanies cell death; however, its role in cell death processes remains unclear. This can be attributed to studying vacuolization at the level of morphology for many years. At the same time, new data on the molecular mechanisms of the vacuole formation and structure have become available. In addition, numerous examples of the association between vacuolization and previously unknown cell death types have been reported. Here, we review these data to make a deeper insight into the role of cytoplasmic vacuolization in cell death and survival.

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“…As mentioned earlier, AMPK stimulates hepatic fatty acid oxidation and ketogenesis, since it lowers malonyl-CoA liver content, thereby permitting fatty acid transport to the mitochondria, where they suffer oxidation [30] . Ethanol exerts an inhibitory effect on AMPK [54] and HCV also downregulates AMPK [29] . In a study performed on 30 patients infected with HCV it was found that mitochondrial β-oxidation of fatty acids was impaired and that this impairment was related to serum levels of HCV core protein [8] .…”

Section: Inhibition Of Fatty Acid Oxidationmentioning

confidence: 99%

“…Ethanol inhibitis sirtuin-1 activity, therefore increasing the lipogenic effect of SREBP 1-c [26] . HCV exerts a similar effect [29] . Sirtuin activity is coupled to that of AMP-activated kinase (AMPK), an enzyme that phosphorylates and, thus, inhibits, acetyl-CoA carboxylase, interrupting the formation of malonyl-CoA, a key step for fatty acids synthesis, and preserving cellular content in NAD [30] .…”

Section: Inhibition Of Fatty Acid Oxidationmentioning

confidence: 99%

Liver steatosis in hepatitis C patients

González‐Reimers¹

2015

WJH

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would affect HCV patients who are also obese or diabetics. In fact, several genotypes exert metabolic effects which overlap with some of those observed in the metabolic syndrome. In this review we will analyse the pathogenic pathways involved in the development of steatosis in HCV patients. Several cytokines and adipokines also become activated and are involved in "pure" steatosic effects, in addition to inflammation. They are probably responsible for the evolution of simple steatosis to steatohepatitis, making it difficult to explain why such alterations only affect a proportion of steatosic patients. Core tip: Chronic hepatitis C virus (HCV) infection can lead to steatosis and steatohepatitis. Increased liver triglyceride synthesis is mediated by several transcription factors such as sterol regulatory elementbinding protein (SREBP) whose expression is enhanced, in turn, by HCV core protein. Chronic HCV infection is also associated with insulin resistance that seems to be selective because although it activates systemic lipolysis, it increases triglyceride synthesis within the liver. This is due to the stimulatory effect of insulin on SREBP. It remains to be answered why not all patients with HCV infection and steatosis develop steatohepatitis despite early cytokine activation and metabolic derangements. AbstractThere is controversy regarding some aspects of hepatitis C virus (HCV) infection-associated liver steatosis, and their relationship with body fat stores. It has classically been found that HCV, especially genotype 3, exerts direct metabolic effects which lead to liver steatosis. This supports the existence of a so called viral steatosis and a metabolic steatosis, which REVIEWSubmit a

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Hepatitis C virus core protein induces hepatic metabolism disorders through down-regulation of the SIRT1–AMPK signaling pathway

Cited by 51 publications

References 23 publications

DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target

DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target

Cytoplasmic vacuolization in cell death and survival

Liver steatosis in hepatitis C patients

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