Hepatitis B virus X protein induces lipogenic transcription factor SREBP1 and fatty acid synthase through the activation of nuclear receptor LXRα

2008 ◽  
Vol 416 (2) ◽  
pp. 219-230 ◽  
Author(s):  
KyeongJin Kim ◽  
Kook Hwan Kim ◽  
Hyeong Hoe Kim ◽  
JaeHun Cheong
Keyword(s):  
Fatty Acid ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Lipid Accumulation ◽  
Fatty Acid Synthase ◽  
Molecular Mechanisms ◽  
Regulatory Element ◽  
Liver Lipid ◽  
Hepatic Cells ◽  
B Virus

HBV (hepatitis B virus) is a primary cause of chronic liver disease, which frequently results in hepatitis, cirrhosis and ultimately HCC (hepatocellular carcinoma). Recently, we showed that HBx (HBV protein X) expression induces lipid accumulation in hepatic cells mediated by the induction of SREBP1 (sterol-regulatory-element-binding protein 1), a key regulator of lipogenic genes in the liver. However, the molecular mechanisms by which HBx increases SREBP1 expression and transactivation remain to be clearly elucidated. In the present study, we demonstrated that HBx interacts with LXRα (liver X receptor α) and enhances the binding of LXRα to LXRE (LXR-response element), thereby resulting in the up-regulation of SREBP1 and FAS (fatty acid synthase) in the presence or absence of the LXR agonist T0901317 in the hepatic cells and HBx-transgenic mice. Furthermore, HBx also augments the ability to recruit ASC2 (activating signal co-integrator 2), a transcriptional co-activator that controls liver lipid metabolic pathways, to the LXRE with LXRα. These studies place LXRα in a key position within the HBx-induced lipogenic pathways, and suggest a molecular mechanism through which HBV infection can stimulate the SREBP1-mediated control of hepatic lipid accumulation.

scholarly journals Phloretin ameliorates hepatic steatosis through regulation of lipogenesis and Sirt1/AMPK signaling in obese mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Chian-Jiun Liou ◽  
Shu-Ju Wu ◽  
Szu-Chuan Shen ◽  
Li-Chen Chen ◽  
Ya-Ling Chen ◽  
...  
Keyword(s):  
Oleic Acid ◽  
Fatty Acid ◽  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Fatty Acid Synthase ◽  
Regulatory Element ◽  
Liver Lipid ◽  
Obese Mice ◽  
Alcoholic Fatty Liver

Abstract Background Phloretin is isolated from apple trees and could increase lipolysis in 3T3-L1 adipocytes. Previous studies have found that phloretin could prevent obesity in mice. In this study, we investigated whether phloretin ameliorates non-alcoholic fatty liver disease (NAFLD) in high-fat diet (HFD)-induced obese mice, and evaluated the regulation of lipid metabolism in hepatocytes. Methods HepG2 cells were treated with 0.5 mM oleic acid to induce lipid accumulation, and then treated with phloretin to evaluate the molecular mechanism of lipogenesis. In another experiment, male C57BL/6 mice were fed normal diet or HFD (60% fat, w/w) for 16 weeks. After the fourth week, mice were treated with or without phloretin by intraperitoneal injection for 12 weeks. Results Phloretin significantly reduced excessive lipid accumulation and decreased sterol regulatory element-binding protein 1c, blocking the expression of fatty acid synthase in oleic acid-induced HepG2 cells. Phloretin increased Sirt1, and phosphorylation of AMP activated protein kinase to suppress acetyl-CoA carboxylase expression, reducing fatty acid synthesis in hepatocytes. Phloretin also reduced body weight and fat weight compared to untreated HFD-fed mice. Phloretin also reduced liver weight and liver lipid accumulation and improved hepatocyte steatosis in obese mice. In liver tissue from obese mice, phloretin suppressed transcription factors of lipogenesis and fatty acid synthase, and increased lipolysis and fatty acid β-oxidation. Furthermore, phloretin regulated serum leptin, adiponectin, triglyceride, low-density lipoprotein, and free fatty acid levels in obese mice. Conclusions These findings suggest that phloretin improves hepatic steatosis by regulating lipogenesis and the Sirt-1/AMPK pathway in the liver.

PPARγ2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes

2005 ◽  
Vol 288 (6) ◽  
pp. E1195-E1205 ◽  
Author(s):  
Susan E. Schadinger ◽  
Nancy L. R. Bucher ◽  
Barbara M. Schreiber ◽  
Stephen R. Farmer
Keyword(s):  
Fatty Acid ◽  
Cell Line ◽  
Lipid Accumulation ◽  
Fatty Acid Synthase ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Binding Protein ◽  
Regulatory Element ◽  
Fatty Acid Binding ◽  
Triacylglycerol Synthesis

Peroxisome proliferator-activated receptor-γ (PPARγ) is considered to be one of the master regulators of adipocyte differentiation. PPARγ2 is abundantly expressed in mature adipocytes and is elevated in the livers of animals that develop fatty livers. The aim of this study was to determine the ability of PPARγ2 to induce lipid accumulation in hepatocytes and to delineate molecular mechanisms driving this process. The hepatic cell line AML-12 was used to generate a cell line stably expressing PPARγ2. Oil Red O staining revealed that PPARγ2 induces lipid accumulation in hepatocytes. This phenotype is accompanied by a selective upregulation of several adipogenic and lipogenic genes including adipose differentiation-related protein (ADRP), adipocyte fatty acid-binding protein 4, sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase (FAS), and acetyl-CoA carboxylase, genes whose expression levels are known to increase in steatotic livers of ob/ob mice. Furthermore, the PPARγ2-regulated induction of both SREBP-1 and FAS parallels an increase in de novo triacylglycerol synthesis in hepatocytes. Triacylglycerol synthesis and lipid accumulation are further enhanced by culturing hepatocytes with troglitazone in the absence of exogenous lipids. These results correspond with an increase in the lipid droplet protein, ADRP, and the data demonstrate that ADRP functions to coat lipid droplets in hepatocytes as observed by confocal microscopy. Taken together, these observations propose a role for PPARγ2 as an inducer of steatosis in hepatocytes and suggest that this phenomenon occurs through an induction of pathways regulating de novo lipid synthesis.

scholarly journals Hepatitis B Virus Replication Is Associated with an HBx-Dependent Mitochondrion-Regulated Increase in Cytosolic Calcium Levels

2007 ◽  
Vol 81 (21) ◽  
pp. 12061-12065 ◽  
Author(s):  
Stephanie L. McClain ◽  
Amy J. Clippinger ◽  
Rebecca Lizzano ◽  
Michael J. Bouchard
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Molecular Mechanisms ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cytosolic Calcium ◽  
Hbv Replication ◽  
B Virus

ABSTRACT The nonstructural hepatitis B virus (HBV) protein HBx has an important role in HBV replication and in HBV-associated liver disease. Many activities have been linked to HBx expression; however, the molecular mechanisms underlying many of these activities are unknown. One proposed HBx function is the regulation of cytosolic calcium. We analyzed calcium levels in HepG2 cells that expressed HBx or replicating HBV, and we demonstrated that HBx, expressed in the absence of other HBV proteins or in the context of HBV replication, elevates cytosolic calcium. We linked this elevation of cytosolic calcium to the association of HBx with the mitochondrial permeability transition pore.

scholarly journals Hepatitis B Virus Pre-S Gene Deletions and Pre-S Deleted Proteins: Clinical and Molecular Implications in Hepatocellular Carcinoma

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 862
Author(s):  
Yueh-Te Lin ◽  
Long-Bin Jeng ◽  
Wen-Ling Chan ◽  
Ih-Jen Su ◽  
Chiao-Fang Teng
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Molecular Mechanisms ◽  
Incidence Rates ◽  
Gene Deletions ◽  
S Gene ◽  
B Virus ◽  
Potential Applications ◽  
Prevention And Therapy

Hepatocellular carcinoma (HCC) is one of the most frequent and fatal human cancers worldwide and its development and prognosis are intimately associated with chronic infection with hepatitis B virus (HBV). The identification of genetic mutations and molecular mechanisms that mediate HBV-induced tumorigenesis therefore holds promise for the development of potential biomarkers and targets for HCC prevention and therapy. The presence of HBV pre-S gene deletions in the blood and the expression of pre-S deleted proteins in the liver tissues of patients with chronic hepatitis B and HBV-related HCC have emerged as valuable biomarkers for higher incidence rates of HCC development and a higher risk of HCC recurrence after curative surgical resection, respectively. Moreover, pre-S deleted proteins are regarded as important oncoproteins that activate multiple signaling pathways to induce DNA damage and promote growth and proliferation in hepatocytes, leading to HCC development. The signaling molecules dysregulated by pre-S deleted proteins have also been validated as potential targets for the prevention of HCC development. In this review, we summarize the clinical and molecular implications of HBV pre-S gene deletions and pre-S deleted proteins in HCC development and recurrence and highlight their potential applications in HCC prevention and therapy.

scholarly journals Woodchuck Hepatitis Virus Contains a Tripartite Posttranscriptional Regulatory Element

1998 ◽  
Vol 72 (6) ◽  
pp. 5085-5092 ◽  
Author(s):  
John E. Donello ◽  
Jonathan E. Loeb ◽  
Thomas J. Hope
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatitis Virus ◽  
Regulatory Element ◽  
Deletion Analysis ◽  
Woodchuck Hepatitis Virus ◽  
B Virus ◽  
Cytoplasmic Accumulation ◽  
Posttranscriptional Regulatory Element

ABSTRACT The hepatitis B virus posttranscriptional regulatory element (HBVPRE) is a cis-acting RNA element that partially overlaps with enhancer I and is required for the cytoplasmic accumulation of HBV surface RNAs. We find that the closely related woodchuck hepatitis virus (WHV), which has been shown to lack a functional enhancer I, also contains a posttranscriptional regulatory element (WPRE). Deletion analysis suggests that the WPRE consists of three independent subelements. Comparison of the bipartite HBVPRE and tripartite WPRE activities reveals that the tripartite WPRE is two to three times more active than the bipartite HBVPRE. Mutation of a single WPRE subelement decreases WPRE activity to the level of the HBVPRE. Bipartite and tripartite chimeras of the WPRE and HBVPRE possess activities which suggest that elements containing three subelements are posttranscriptionally stronger than those containing two. These data demonstrate that the posttranscriptional regulatory element is conserved within the mammalian hepadnaviruses and that its strength is determined by the number of subelements within the RNA.

scholarly journals Polyphenol-Rich Extracts from Toona sinensis Bark and Fruit Ameliorate Free Fatty Acid-Induced Lipogenesis through AMPK and LC3 Pathways

2019 ◽  
Vol 8 (10) ◽  
pp. 1664 ◽  
Author(s):  
Yung-Chia Chen ◽  
Hsin-Ju Chen ◽  
Bu-Miin Huang ◽  
Yu-Chi Chen ◽  
Chi-Fen Chang
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Free Fatty Acid ◽  
Protein Expression ◽  
Lipid Accumulation ◽  
Fatty Acid Synthase ◽  
Regulatory Element ◽  
Autophagic Flux ◽  
Alcoholic Fatty Liver ◽  
Toona Sinensis

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease found worldwide. The present study aimed to evaluate the mechanisms of inhibiting lipid accumulation in free fatty acid (FFA)-treated HepG2 cells caused by bark and fruit extracts of Toona sinensis (TSB and TSF). FFA induced lipid and triglyceride (TG) accumulation, which was attenuated by TSB and TSF. TSB and/or TSF promoted phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-coA carboxylase and peroxisome proliferator-activated receptor alpha upregulation. Furthermore, TSB and TSF suppressed FFA-induced liver X receptor, sterol regulatory element-binding transcription protein 1, fatty acid synthase, and stearoyl-CoA desaturase 1 protein expression. Moreover, TSB and/or TSF induced phosphorylation of Unc-51 like autophagy-activating kinase and microtubule-associated protein 1A/1B-light chain 3 expressions. Therefore, TSB and TSF relieve lipid accumulation by attenuating lipogenic protein expression, activating the AMPK pathway, and upregulating the autophagic flux to enhance lipid metabolism. Moreover, TSB and TSF reduced TG contents, implying the therapeutic use of TSB and TSF in NAFLD.

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