Expression profile of lipid metabolism‐associated genes in hepatitis C virus‐infected human liver

Fujino, Tatsuya; Nakamuta, Makoto; Yada, Ryoko; Aoyagi, Yoko; Yasutake, Kenichiro; Kohjima, Motoyuki; Fukuizumi, Kunitaka; Yoshimoto, Tsuyoshi; Harada, Naohiko; Yada, Masayoshi; Kato, Masaki; Kotoh, Kazuhiro; Taketomi, Akinobu; Maehara, Yoshihiko; Nakashima, Mitsuyoshi; Enjoji, Munechika

doi:10.1111/j.1872-034x.2010.00700.x

Cited by 45 publications

(48 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…On the other hand, HCV infection profoundly disturbs lipid metabolism pathways (11). HCV patients exhibit enhanced lipogenesis (12), consistent with in vitro results showing that HCV infection upregulates genes encoding sterol regulatory element binding protein 1c (SREBP-1c) and fatty acid synthase (FASN), both important for the intracellular lipid synthesis pathway (13)(14)(15)(16). More recently, the 3= untranslated region (UTR) of HCV was shown to, upon binding of DDX3, activate IB kinase ␣ and trigger biogenesis of LDs (17).…”

supporting

confidence: 63%

Hepatitis C Virus-Induced Degradation of Cell Death-Inducing DFFA-Like Effector B Leads to Hepatic Lipid Dysregulation

Lee

Alsagheir

et al. 2016

J Virol

View full text Add to dashboard Cite

Individuals chronically infected with hepatitis C virus (HCV) commonly exhibit hepatic intracellular lipid accumulation, termed steatosis. HCV infection perturbs host lipid metabolism through both cellular and virus-induced mechanisms, with the viral core protein playing an important role in steatosis development. We have recently identified a liver protein, the cell deathinducing DFFA-like effector B (CIDEB), as an HCV entry host dependence factor that is downregulated by HCV infection in a cell culture model. In this study, we investigated the biological significance and molecular mechanism of this downregulation. HCV infection in a mouse model downregulated CIDEB in the liver tissue, and knockout of the CIDEB gene in a hepatoma cell line results in multiple aspects of lipid dysregulation that can contribute to hepatic steatosis, including reduced triglyceride secretion, lower lipidation of very-low-density lipoproteins, and increased lipid droplet (LD) stability. The potential link between CIDEB downregulation and steatosis is further supported by the requirement of the HCV core and its LD localization for CIDEB downregulation, which utilize a proteolytic cleavage event that is independent of the cellular proteasomal degradation of CIDEB. IMPORTANCE Our data demonstrate that HCV infection of human hepatocytes in vitro and in vivo results in CIDEB downregulation via a proteolytic cleavage event. Reduction of CIDEB protein levels by HCV or gene editing, in turn, leads to multiple aspects of lipid dysregulation, including LD stabilization. Consequently, CIDEB downregulation may contribute to HCV-induced hepatic steatosis.H epatitis C virus (HCV) is a positive-strand RNA virus and a significant human pathogen. Chronic HCV infection causes liver complications, such as steatosis, cirrhosis, and hepatocellular carcinoma. The arrival of new directly acting antivirals (DAAs) has resulted in markedly improved virologic response in patients with access to these new drugs, but the high cost of the new therapy and the low diagnosis rate of HCV-infected individuals present new challenges for hepatitis C management (1). Furthermore, chronic liver damage can persist even after the infection has been cleared, so HCV pathogenesis remains an area of research highly significant for human health.The HCV life cycle and pathogenesis are intimately linked to host lipid metabolism (2). On one hand, lipids are involved in multiple stages of the infection cycle. HCV virions are assembled on lipid droplets (LDs) (3) and associated with host lipoproteins to form lipoviral particles (LVP) for infection (4). The productive entry of HCV is aided by several molecules involved in lipid uptake (5-7); replication of HCV genome critically depends on a lipid kinase (8, 9) and is regulated by lipid peroxidation (10). On the other hand, HCV infection profoundly disturbs lipid metabolism pathways (11). HCV patients exhibit enhanced lipogenesis (12), consistent with in vitro results showing that HCV infection upregulates genes encoding sterol...

show abstract

supporting

confidence: 63%

Hepatitis C Virus-Induced Degradation of Cell Death-Inducing DFFA-Like Effector B Leads to Hepatic Lipid Dysregulation

Lee

Alsagheir

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…FASN expression is significantly increased in HCV-infected livers (37), and serum FASN concentrations are significantly increased in patients with chronic HCV infection (38,39). FASN is also upregulated in HCV-infected Huh7 cells (18).…”

Section: Discussionmentioning

confidence: 90%

Hepatitis C Virus Replication Is Modulated by the Interaction of Nonstructural Protein NS5B and Fatty Acid Synthase

Huang

Tseng

Liao

et al. 2013

J Virol

View full text Add to dashboard Cite

Hepatitis C virus (HCV) is a positive-stranded RNA virus classified in the Hepacivirus genus in the family Flaviviridae. The 9.6-kb viral RNA genome encodes a precursor polyprotein that is processed to generate at least 10 viral proteins, including structural proteins (core, E1, E2, and p7) and nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (1). The NS5B RNA polymerase, together with other nonstructural viral proteins (NS3, NS4A, NS4B, and NS5A) and host factors, constitutes the active replication complexes (RC) for viral RNA replication. These proteins are directly or indirectly associated with the endoplasmic reticulum (ER)-derived structure called the "membranous web," where replication occurs (2, 3). However, the exact host factors and detailed interactions within the RC remain to be determined.HCV infection usually causes chronic hepatitis and frequently leads to cirrhosis and hepatocellular carcinoma (HCC). Besides, HCV-induced end-stage liver disease is an important indication for liver transplantation in most of the Western countries (4, 5). At present, no effective vaccine to prevent HCV infection is available. The current treatment strategies for HCV infection are valid only for individuals with a particular single nucleotide polymorphism (SNP) in the interleukin-28B gene or for infections caused by certain viral genotypes (6). Accordingly, the prevalence of hepatic steatosis in HCV-infected patients is much higher than that in the general population or in hepatitis B virus (HBV)-infected patients (7). Hepatic steatosis has also been reported to be associated with an increased rate of HCC in chronic hepatitis C patients (8).Lipid metabolic pathways are essential for the entry, secretion, and replication of HCV. For example, apolipoprotein E (apoE) is essential for the production of HCVcc (HCV produced in cell culture) and for viral entry (9, 10). Downregulation of apoA-I decreases levels of HCV replication and viral particle production in cell culture (11). HCV coopts the secretory pathway of very low density lipoprotein (VLDL) for its own secretion (12, 13). Moreover, HCV replication is regulated through induction of lipogenic gene expression in HCV replicon cells (14) or geranylgeranylation of host proteins required for HCV RNA replication (15,16). Fatty acid synthesis is also required for HCV RNA replication (14). Inhibition of fatty acid synthase (FASN) by cerulenin (17) or C75 (18) reduces the replication of subgenomic HCV replicons as well as JFH-1-based HCVcc virion production. Although the underlying mechanisms are not yet completely understood, these studies imply that FASN is essential for HCV replication.In this study, HCV NS5B was used as the bait to screen for NS5B-interacting proteins that are present in Huh7 hepatoma cell lysates. After mass spectrophotometric analysis, FASN was found to interact with NS5B, and this interaction was further confirmed in vitro and in vivo. Our data indicate that FASN interacts with NS5B to enhance NS5B RNA-dependent RNA polymerase (RdRp) act...

show abstract

“…These demands are provide by an increase on genes activity related to lipid biosynthesis, while the low-density lipoprotein receptor activity is reduced. [31] In addition, HCV infection induces synthesis of fatty acids, which increases lipogenesis and contribute to the steatosis and the tumorigenesis. [32]…”

Section: Discussionmentioning

confidence: 99%

Orange juice as dietary source of antioxidants for patients with hepatitis C under antiviral therapy

Gonçalves

Lima

Ferreira

et al. 2017

Food & Nutrition Research

View full text Add to dashboard Cite

Background: HCV causes alterations in liver metabolism, resulting in biochemical and nutritional disorders. Supplementation with antioxidants has been suggested to minimize the diseases effects. Objective: This study assessed whether orange juice, a source of citrus flavonoids and vitamin C, may contribute to the treatment of patients with chronic hepatitis C. Design: Anthropometric, hemodynamic, dietary, and biochemical parameters, CRP and liver enzymes were measured in 43 adult patients of both genders who were diagnosed with chronic hepatitis C and were under antiviral therapy. Twenty-three patients were supplemented with orange juice for eight consecutive weeks, while 20 were enrolled as control group. Results: Following regular use of orange juice, no alterations were found in body mass, fat, and waist circumference. The serum levels of total cholesterol, LDL-cholesterol, CRP and parameters of oxidative stress decreased in the orange juice group. Furthermore, the levels of the liver enzyme AST decreased in those who had high levels before the intervention. Conclusion: The orange juice was a convenient food in the diet of patients due to the increase in antioxidant capacity and decreased inflammation and cholesterol in blood serum, in addition to maintaining body mass, which protect against the harmful effects caused by the chronic hepatitis C virus.

show abstract

Expression profile of lipid metabolism‐associated genes in hepatitis C virus‐infected human liver

Cited by 45 publications

References 30 publications

Hepatitis C Virus-Induced Degradation of Cell Death-Inducing DFFA-Like Effector B Leads to Hepatic Lipid Dysregulation

Hepatitis C Virus-Induced Degradation of Cell Death-Inducing DFFA-Like Effector B Leads to Hepatic Lipid Dysregulation

Hepatitis C Virus Replication Is Modulated by the Interaction of Nonstructural Protein NS5B and Fatty Acid Synthase

Orange juice as dietary source of antioxidants for patients with hepatitis C under antiviral therapy

Contact Info

Product

Resources

About