Hepatitis B Virus X Protein Induces Hepatic Steatosis Via Transcriptional Activation of SREBP1 and PPARγ

Kim, Kook Hwan; Shin, Hye–Jun; Kim, Kyeongjin; Choi, Hyun Rim; Rhee, Sang Hoon; Moon, Hyung–Bae; Kim, Hyeong Hoe; Yang, Ung Suk; Yu, Dae‐Yeul; Cheong, JaeHun

doi:10.1053/j.gastro.2007.03.039

Cited by 259 publications

(231 citation statements)

References 56 publications

Supporting

Mentioning

215

Contrasting

Unclassified

Order By: Relevance

“…19 PPARa, for example, has recently been implicated in HCV-induced hepatocarcinogenesis, 33 and hepatic steatosis is induced through HBx-dependent activation of PPARg by HBV X protein. 34 Although adipophilin has been reported to be influenced by PPARa, eg, in liver, perilipin is upregulated under the presence of PPARg in adipocytes. Using rtPCR analysis, we detected transcripts of both PPARa and PPARg in human HCCs concomitant with perilipin, adipophilin, and TIP47 expression, suggesting PPARs as potential regulators of altered PAT-expression in neoplastic steatogenesis.…”

Section: Discussionmentioning

confidence: 99%

Lipid droplet-associated PAT-proteins show frequent and differential expression in neoplastic steatogenesis

et al. 2010

View full text Add to dashboard Cite

In many human cancers, lipogenic pathways are activated; in some tumors, such as hepatocellular carcinoma, this is reflected by the presence of visible lipid droplets. Yet, the biology of steatogenesis in malignant tumors is largely unknown. We have recently shown that lipid droplet-associated proteins of the PAT-family, named after their constituents perilipin (perilipin 1), adipophilin (perilipin 2), and TIP47 (perilipin 3) are differentially expressed in hepatic steatogenesis. We have comprehensively investigated PAT-expression in neoplastic steatogenesis as well as in respective normal tissues with immunohistology and electron microscopy as well as protein biochemical and molecular biological methods. By staining for PAT-proteins, we found lipid droplet accumulation to be a frequent phenomenon of carcinoma cells. Although adipophilin and TIP47 stained almost ubiquitously the rim of lipid droplets in various tumor types, especially those with clear cell phenotype, perilipin was restricted to lipid droplets of hepatocellular adenoma and carcinoma, sebaceous adenoma and carcinoma, and lipomatous tumors. In hepatocellular carcinoma, perilipin, adipophilin, and TIP47 were coexpressed, and showed regional heterogeneity with a predominantly mutually exclusive localization pattern. In step-wise carcinogenesis, adipophilin expression correlated with the proliferation rate and was upregulated during early tumorigenesis, whereas perilipin was often lost during hepatocarcinogenesis. In conclusion, expression analysis of PAT-proteins showed that by far more carcinomas contain (PAT-positive) lipid droplets than expected by conventional light microscopy. PAT-proteins, such as perilipin, are differentially expressed in different tumor types and thus may support diagnostic considerations. Because inhibition of lipogenesis has been shown to exert antineoplastic effects, PAT-proteins may represent targets for interventive strategies.

show abstract

Section: Discussionmentioning

confidence: 99%

Lipid droplet-associated PAT-proteins show frequent and differential expression in neoplastic steatogenesis

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Several studies have shown that activations of PPAR by HCV core protein and hepatitis B virus X protein were required for hepatic accumulation of lipid (19,27,43). Because PPAR␣ regulates constitutive transcription of genes encoding fatty acid metabolizing enzymes (44), and PPAR␥ is a master regulator of genes involved in fatty acid and glucose metabolism (45), further studies are required to determine the role of NS4B in PPAR regulation.…”

Section: Discussionmentioning

confidence: 99%

“…pcDNA3.1-Flag-SREBP-1a (human, amino acids 1-490), pGL2B-FAS-luc (fatty acid synthase promoter), and pSynSRE-luc (hamster HMG-CoA synthase promoter) vectors were kindly provided by Dr. T. R. Osborne (24 -26). pcDNA3-HA-SREBP-1c (human, amino acids 1-447) was described previously (27). pBP1c550-Luc, the luciferase gene containing 550-bp fragments of the mouse SREBP-1c promoter, was a gift from Dr. H. Shimano (28).…”

Section: Methodsmentioning

confidence: 99%

Hepatitis C Virus Nonstructural 4B Protein Modulates Sterol Regulatory Element-binding Protein Signaling via the AKT Pathway

Park

Jun

Wakita

et al. 2009

Journal of Biological Chemistry

133

106

View full text Add to dashboard Cite

Hepatitis C virus (HCV) infection is often associated with hepatic steatosis and yet the molecular mechanisms of HCVassociated steatosis are poorly understood. Because sterol regulatory element-binding proteins (SREBPs) are the major transcriptional factors in lipogenic gene expression including fatty acid synthase (FAS), we examined the effects of HCV nonstructural proteins on the signaling pathways of SREBP. In this study, we demonstrated that HCV nonstructural 4B (NS4B) protein increased the transcriptional activities of SREBPs. We also showed that HCV NS4B enhanced the protein expression levels of SREBPs and FAS. This was further confirmed in the context of viral RNA replication and HCV infection. The up-regulation of both SREBP and FAS by NS4B protein required phosphatidylinositol 3-kinase activity. We also demonstrated that NS4B protein induced a lipid accumulation in hepatoma cells. In addition, NS4B protein synergistically elevated the transcriptional activity of HCV core-mediated SREBP-1. These results strongly suggest that NS4B may play an important role in HCV-associated liver pathogenesis by modulating the SREBP signaling pathway.

show abstract

“…11 Recently, HBx was shown to cause lipid accumulation in hepatic cells, mediated by the activation of SREBP-1 and peroxisome proliferator-activated receptor ␥ (PPAR␥). 12 The LXR plays an important role in the regulation of the expression of genes involved in the metabolism of lipids and cholesterol. 13,14 Two LXR subtypes, LXR␣ (nuclear receptor subfamily 1, group H, member 3) and LXR␤ (nuclear receptor subfamily 1, group H, member 2), have been identified that form heterodimers with the retinoid X receptor (RXR) and bind specific DNA sequences, that is, the liver X receptor response element (LXRE).…”

mentioning

confidence: 99%

Liver X receptor mediates hepatitis B virus X protein–induced lipogenesis in hepatitis B virus–associated hepatocellular carcinoma #

Na¹,

Shin²,

Roh³

et al. 2009

Hepatology

136

105

View full text Add to dashboard Cite

H epatitis B, caused by hepatitis B virus (HBV) infection, is very common in Asia, Africa, and the Middle East. It is estimated that there are 280 million carriers worldwide, representing more than 5% of the global population. Chronic infection with HBV is a major risk factor for the development of hepatocellular carcinoma (HCC); however, the mechanism by which HBV induces events leading to HCC has not been clearly elucidated. The HBV genome consists of four overlapping open reading frames encoding DNA polymerase, surface antigen, core protein, and a regulatory X protein [hepatitis B virus X protein (HBx)].

show abstract

Hepatitis B Virus X Protein Induces Hepatic Steatosis Via Transcriptional Activation of SREBP1 and PPARγ

Cited by 259 publications

References 56 publications

Lipid droplet-associated PAT-proteins show frequent and differential expression in neoplastic steatogenesis

Lipid droplet-associated PAT-proteins show frequent and differential expression in neoplastic steatogenesis

Hepatitis C Virus Nonstructural 4B Protein Modulates Sterol Regulatory Element-binding Protein Signaling via the AKT Pathway

Liver X receptor mediates hepatitis B virus X protein–induced lipogenesis in hepatitis B virus–associated hepatocellular carcinoma #

Contact Info

Product

Resources

About