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liver can s er

Yujing Zhang, Fang Xiao, Xinmin Liu, Kaihua Liu, Xiaoxin Zhou, Caigao Zhong
The occupational and environmental toxicant hexavalent chromium [Cr(VI)] can cause severe damage to the liver; however, the exact mechanisms associated with its toxicity have not been thoroughly demonstrated. In the present study, the underlying mechanisms of Cr(VI)-induced hepatotoxicity were investigated. Our results showed that Cr(VI) inhibited the growth and proliferation of L-02 hepatocytes. Further study revealed that Cr(VI) significantly induced S-phase cell cycle arrest and apoptosis accompanying with the overproduction of reactive oxygen species (ROS)...
March 18, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Min-Ran Li, Huan-Wei Zheng, Jian-Hua Lu, Shun-Mao Ma, Li-Hong Ye, Zhi-Quan Liu, Hai-Cong Zhang, Yun-Yan Liu, Ying Lv, Yan Huang, Er-Hei Dai, Dian-Xing Sun
BACKGROUND: Previous studies have revealed that hepatitis B core antibody (anti-HBc) levels vary throughout the different phases of treatment-naïve chronic hepatitis B (CHB) patients and can be used as a predictor of treatment response in both interferon-α and nucleoside analogue therapies. However, few data have been published regarding the relationship between quantitative anti-HBc (qAnti-HBc) levels and liver fibrosis in patients with CHB. RESULTS: A total of 489 HBeAg-positive (HBeAg (+)) and 135 HBeAg-negative (HBeAg (-)) patients were recruited...
February 14, 2017: Oncotarget
Paul Lebeau, Ali Al-Hashimi, Sudesh Sood, Šárka Lhoták, Pei Yu, Gabriel Gyulay, Guillaume Paré, S R Wayne Chen, Bernardo Trigatti, Annik Prat, Nabil G Seidah, Richard C Austin
Accumulating evidence implicates endoplasmic reticulum (ER) stress as a mediator of impaired lipid metabolism, thereby contributing to fatty liver disease and atherosclerosis. Previous studies demonstrated that ER stress can activate the sterol regulatory element-binding protein-2 (SREBP2), an ER-localized transcription factor that directly up-regulates sterol regulatory genes, including PCSK9 Given that PCSK9 contributes to atherosclerosis by targeting low density lipoprotein (LDL) receptor (LDLR) degradation, this study investigates a novel mechanism by which ER stress plays a role in lipid metabolism by examining its ability to modulate PCSK9 expression...
January 27, 2017: Journal of Biological Chemistry
Ismail Çimen, Begüm Kocatürk, Seda Koyuncu, Özlem Tufanlı, Umut I Onat, Asli D Yıldırım, Onur Apaydın, Şeyma Demirsoy, Zaliha G Aykut, Uyen T Nguyen, Steven M Watkins, Gökhan S Hotamışlıgil, Ebru Erbay
De novo lipogenesis (DNL), the conversion of glucose and other substrates to lipids, is often associated with ectopic lipid accumulation, metabolic stress, and insulin resistance, especially in the liver. However, organ-specific DNL can also generate distinct lipids with beneficial metabolic bioactivity, prompting a great interest in their use for the treatment of metabolic diseases. Palmitoleate (PAO), one such bioactive lipid, regulates lipid metabolism in liver and improves glucose utilization in skeletal muscle when it is generated de novo from the obese adipose tissue...
September 28, 2016: Science Translational Medicine
Jennifer A Dickens, Adriana Ordóñez, Joseph E Chambers, Alison J Beckett, Vruti Patel, Elke Malzer, Caia S Dominicus, Jayson Bradley, Andrew A Peden, Ian A Prior, David A Lomas, Stefan J Marciniak
α1-Antitrypsin is a serine protease inhibitor produced in the liver that is responsible for the regulation of pulmonary inflammation. The commonest pathogenic gene mutation yields Z-α1-antitrypsin, which has a propensity to self-associate forming polymers that become trapped in inclusions of endoplasmic reticulum (ER). It is unclear whether these inclusions are connected to the main ER network in Z-α1-antitrypsin-expressing cells. Using live cell imaging, we found that despite inclusions containing an immobile matrix of polymeric α1-antitrypsin, small ER resident proteins can diffuse freely within them...
December 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Hao Wang, Ruo-Qiong Sun, Daria Camera, Xiao-Yi Zeng, Eunjung Jo, Stanley M H Chan, Terence P Herbert, Juan C Molero, Ji-Ming Ye
The accumulation of unfolded proteins within the endoplasmic reticulum (ER) causes ER stress and activation of unfolded protein response (UPR). This response can trigger ER-associated degradation and autophagy, which clear unfolded proteins and restore protein homeostasis. Recently, it has become clear that ubiquitination plays an important role in the regulation of autophagy. In the present study, we investigated how the E3 ubiquitin ligase neural precursor cell-expressed, developmentally down-regulated protein 4-2 (Nedd4-2) interacts with ER stress and autophagy...
July 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
V D Baldissera, A F Alves, S Almeida, M Porawski, M Giovenardi
Hepatocellular carcinoma (HCC) is the most common primary tumor of liver and its incidence continues to increase worldwide. HCC is a disease with multifactorial causes and genetic variability has been discussed as a risk factor for its development. Liver is a hormone-sensitive organ and therefore is influenced by gonadal hormones, such as estrogen. Estrogen is known to participate in various biological functions, but its role in development of HCC, on the other hand, is controversial and presents evidence suggesting a role as both a carcinogen and protective effect in liver...
January 2016: Medical Hypotheses
Jeffrey S Ross, Laurie M Gay, Sahar Nozad, Kai Wang, Siraj M Ali, Ann Boguniewicz, Depinder Khaira, Adrienne Johnson, Julia A Elvin, Jo-Anne Vergilio, James Suh, Vincent A Miller, Philip J Stephens
PURPOSE: Pure mucinous breast carcinoma (pmucBC) is a distinctive variant of breast cancer (BC) featuring an excellent overall prognosis. However, on rare occasions, pmucBC pursues an aggressive clinical course. We queried whether comprehensive genomic profiling (CGP) would uncover clinically relevant genomic alterations (CRGA) that could lead to targeted therapy treatment for patients with an advanced and metastatic form of pmucBC. METHODS: From a series of 51,238 total cancer samples, which included 5605 cases of clinically advanced BC and 22 cases of stage IV pmucBC, DNA was extracted from 40 microns of FFPE sections...
January 2016: Breast Cancer Research and Treatment
Jiajia Zheng, Suzhen Jiang, Fengmin Lu
We investigated the biological effect of hepatitis B virus (HBV) rtA181T/sW172* point mutation on HBsAg secretion and the potential mechanisms involved in hepatocarcinogenesis. Full-length HBV wild type (wt) and HBV rtA181T/sW172* expression plasmids were transfected into HepG2 cell lines or were injected into C57BL/6 mice. The extracellular and intracellular expression levels of HBsAg and HBeAg proteins, in mouse serum and liver tissues were detected by ELISA. The localization of the truncated protein was characterized in vitro...
July 22, 2016: Japanese Journal of Infectious Diseases
In-Kyung Lee, Seoung-Ae Lee, Hong Kim, You-Sub Won, Bum-Joon Kim
AIM: To investigate the mechanism of endoplasmic reticulum (ER) stress induction by an occult infection related hepatitis B virus S surface antigen (HBsAg) variant. METHODS: We used an HBsAg variant with lower secretion capacity, which was a KD variant from a Korean subject who was occultly infected with the genotype C. We compared the expression profiles of ER stress-related proteins between HuH-7 cells transfected with HBsAg plasmids of a wild-type and a KD variant using Western blot...
June 14, 2015: World Journal of Gastroenterology: WJG
Insook Jang, Han Byeol Kim, Hojoong Seo, Jin Young Kim, Hyeonjin Choi, Jong Shin Yoo, Jae-woo Kim, Jin Won Cho
O-GlcNAcylation is highly involved in cellular stress responses including the endoplasmic reticulum (ER) stress response. For example, glucosamine-induced flux through the hexosamine biosynthetic pathway can promote ER stress and ER stress inducers can change the total cellular level of O-GlcNAcylation. However, it is largely unknown which component(s) of the unfolded protein response (UPR) is directly regulated by O-GlcNAcylation. In this study, eukaryotic translation initiation factor 2α (eIF2α), a major branch of the UPR, was O-GlcNAcylated at Ser 219, Thr 239, and Thr 241...
August 2015: Biochimica et Biophysica Acta
Anup Ramachandran, Margitta Lebofsky, Hui-Min Yan, Steven A Weinman, Hartmut Jaeschke
Chronic hepatitis C virus (HCV) infection predisposes patients to develop liver failure after acetaminophen (APAP) overdose. Mechanisms involved in this were explored using transgenic mice expressing the HCV structural proteins core, E1 and E2. Treatment of C57BL/6J mice with 200 mg/kg body weight APAP resulted in significant liver injury at 6 h as indicated by elevated ALT levels, focal centrilobular necrosis and nuclear DNA fragmentation. HCV transgenic mice showed a variable response, with approximately half the animals showing exacerbation of all parameters of liver injury, while the other half was protected...
May 2015: Archives of Toxicology
Ndiya Ogba, Nicole G Manning, Brian S Bliesner, S Kelly Ambler, James M Haughian, Mauricio P Pinto, Paul Jedlicka, Kristiina Joensuu, Päivi Heikkilä, Kathryn B Horwitz
INTRODUCTION: Luminal, estrogen receptor-positive (ER(+)) breast cancers can metastasize but lie dormant for years before recurrences prove lethal. Understanding the roles of estrogen (E) or progestin (P) in development of luminal metastases or in arousal from dormancy is hindered by few preclinical models. We have developed such models. METHODS: Immunocompromised, ovariectomized (ovx'd) mice were intracardiac-injected with luminal or basal human breast cancer cells...
2014: Breast Cancer Research: BCR
Krishna S Tummala, Ana L Gomes, Mahmut Yilmaz, Osvaldo Graña, Latifa Bakiri, Isabel Ruppen, Pilar Ximénez-Embún, Vinayata Sheshappanavar, Manuel Rodriguez-Justo, David G Pisano, Erwin F Wagner, Nabil Djouder
Molecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic reduction in hepatocytes protects against diethylnitrosamine (DEN)-induced HCC. URI inhibits aryl hydrocarbon (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes implicated in L-tryptophan/kynurenine/nicotinamide adenine dinucleotide (NAD(+)) metabolism, thereby causing DNA damage at early stages of tumorigenesis...
December 8, 2014: Cancer Cell
Claire H Wilson, Eunüs S Ali, Nathan Scrimgeour, Alyce M Martin, Jin Hua, George A Tallis, Grigori Y Rychkov, Greg J Barritt
Lipid accumulation in hepatocytes can lead to non-alcoholic fatty liver disease (NAFLD), which can progress to non-alcoholic steatohepatitis (NASH) and Type 2 diabetes (T2D). Hormone-initiated release of Ca²⁺ from the endoplasmic reticulum (ER) stores and subsequent replenishment of these stores by Ca²⁺ entry through SOCs (store-operated Ca²⁺ channels; SOCE) plays a critical role in the regulation of liver metabolism. ER Ca²⁺ homoeostasis is known to be altered in steatotic hepatocytes. Whether store-operated Ca²⁺ entry is altered in steatotic hepatocytes and the mechanisms involved were investigated...
March 1, 2015: Biochemical Journal
Wan-Ting Chen, Dat Ha, Gary Kanel, Amy S Lee
Hepatocellular carcinoma (HCC) often results from chronic liver injury and severe fibrosis or cirrhosis, but the underlying molecular pathogenesis is unclear. We previously reported that deletion of glucose regulated protein 94 (GRP94), a major endoplasmic reticulum chaperone, in the bone marrow and liver leads to progenitor/stem cell expansion. Since liver progenitor cell (LPC) proliferation can contribute to liver tumor formation, here we examined the effect of GRP94 deficiency on spontaneous liver tumorigenesis...
August 2014: Neoplasia: An International Journal for Oncology Research
Alexandra K Leamy, Robert A Egnatchik, Masakazu Shiota, Pavlina T Ivanova, David S Myers, H Alex Brown, Jamey D Young
High levels of saturated FAs (SFAs) are acutely toxic to a variety of cell types, including hepatocytes, and have been associated with diseases such as type 2 diabetes and nonalcoholic fatty liver disease. SFA accumulation has been previously shown to degrade endoplasmic reticulum (ER) function leading to other manifestations of the lipoapoptotic cascade. We hypothesized that dysfunctional phospholipid (PL) metabolism is an initiating factor in this ER stress response. Treatment of either primary hepatocytes or H4IIEC3 cells with the SFA palmitate resulted in dramatic dilation of the ER membrane, coinciding with other markers of organelle dysfunction...
July 2014: Journal of Lipid Research
Alexandre Ferro Aissa, Volodymyr Tryndyak, Aline de Conti, Stepan Melnyk, Tarsila Daysy Ursula Hermogenes Gomes, Maria Lourdes Pires Bianchi, S Jill James, Frederick A Beland, Lusania Maria Greggi Antunes, Igor P Pogribny
SCOPE: A compromised nutritional status in methyl-group donors may provoke several molecular alterations triggering the development of nonalcoholic fatty liver disease (NAFLD) in humans and experimental animals. In this study, we investigated a role and the underlying molecular mechanisms of methionine metabolic pathway malfunctions in the pathogenesis of NAFLD. METHODS AND RESULTS: We fed female Swiss albino mice a control (methionine-adequate) diet and two experimental (methionine-deficient or methionine-supplemented) diets for 10 weeks, and the levels of one-carbon metabolites, expression of one-carbon and lipid metabolism genes in the livers were evaluated...
July 2014: Molecular Nutrition & Food Research
E F O'Donnell, D C Koch, W H Bisson, H S Jang, S K Kolluri
Identification of new molecular targets for the treatment of breast cancer is an important clinical goal, especially for triple-negative breast cancer, which is refractory to existing targeted treatments. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known primarily as the mediator of dioxin toxicity. However, the AhR can also inhibit cellular proliferation in a ligand-dependent manner and act as a tumor suppressor in mice, and thus may be a potential anticancer target. To investigate the AhR as an anticancer target, we conducted a small molecule screen to discover novel AhR ligands with anticancer properties...
2014: Cell Death & Disease
Xiao-Hua Yu, Na Jiang, Ping-Bo Yao, Xi-Long Zheng, Francisco S Cayabyab, Chao-Ke Tang
Post-lysosomal cholesterol trafficking is an important, but poorly understood process that is essential to maintain lipid homeostasis. Niemann-Pick type C1 (NPC1), an integral membrane protein on the limiting membrane of late endosome/lysosome (LE/LY), is known to accept cholesterol from NPC2 and then mediate cholesterol transport from LE/LY to endoplasmic reticulum (ER) and plasma membrane in a vesicle- or oxysterol-binding protein (OSBP)-related protein 5 (ORP5)-dependent manner. Mutations in the NPC1 gene can be found in the majority of NPC patients, who accumulate massive amounts of cholesterol and other lipids in the LE/LY due to a defect in intracellular lipid trafficking...
February 15, 2014: Clinica Chimica Acta; International Journal of Clinical Chemistry
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