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Shuixian Du, Linlin Lu, Yingxia Miao, Wenwen Jin, Changfei Li, Yongning Xin, Shiying Xuan
BACKGROUND: Some studties reported that the polymorphism of TM6SF2 gene E167K affects the occurrence and the progression of hepatocytes carcinoma (hepatocellular, HCC). In oeder to investigate the effects of the polymorphism of TM6SF2 gene E167K in the pathogenesis of HCC, we explored its influence on the cell cycle in hepatocellular carcinoma cell HEPA1-6. METHODS: HEPA 1-6 cells which could respectively overexpress TM6SF2 wild type and E167K variant were cultured and HEPA 1-6 cells with zero load plasmids were used as matched control...
April 13, 2017: Lipids in Health and Disease
Zhenghui G Jiang, Elliot B Tapper, Misung Kim, Margery A Connelly, Sarah A Krawczyk, Eric U Yee, Mark A Herman, Kenneth J Mukamal, Michelle Lai
BACKGROUND: Recent genome-wide association studies have identified 2 genetic polymorphisms in association with nonalcoholic fatty liver disease (NAFLD): patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), both of which appear to influence the production of very low density lipoprotein (VLDL). The impact of these genetic variations on lipoprotein metabolism in the setting of nonalcoholic steatohepatitis and liver fibrosis are not fully characterized...
March 30, 2017: Journal of Clinical Gastroenterology
Enoch Cobbina, Fatemeh Akhlaghi
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a "three-hit" process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 has been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD...
March 17, 2017: Drug Metabolism Reviews
Giovanni Musso, Ugo Cipolla, Maurizio Cassader, Silvia Pinach, Francesca Saba, Franco De Michieli, Elena Paschetta, Daria Bongiovanni, Luciana Framarin, Nicola Leone, Mara Berrutti, Floriano Rosina, Stefania Corvisieri, Federica Molinaro, Antonio Sircana, Roberto Gambino
Mechanisms underlying the opposite effects of TM6SF2 rs58542926 C>T polymorphism on liver injury and cardio-metabolic risk in NAFLD are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese, nondiabetic, normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry, an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, incretin GIP, and an OGTT with Minimal Model analysis of glucose homeostasis...
February 27, 2017: Journal of Lipid Research
Panu K Luukkonen, You Zhou, P A Nidhina Haridas, Om P Dwivedi, Tuulia Hyötyläinen, Ashfaq Ali, Anne Juuti, Marja Leivonen, Taru Tukiainen, Linda Ahonen, Emma Scott, Jeremy M Palmer, Johanna Arola, Marju Orho-Melander, Petter Vikman, Quentin M Anstee, Vesa M Olkkonen, Matej Orešič, Leif Groop, Hannele Yki-Järvinen
BACKGROUND: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2(EK/KK)) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common 'obese/metabolic' NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids...
February 21, 2017: Journal of Hepatology
Khaled Thabet, Henry Lik Yuen Chan, Salvatore Petta, Alessandra Mangia, Thomas Berg, Andre Boonstra, Willem P Brouwer, Maria Lorena Abate, Vincent Wai-Sun Wong, Maiiada Nazmy, Janett Fischer, Christopher Liddle, Jacob George, Mohammed Eslam
Chronic hepatitis B (CHB) is characterized by hepatic inflammation that promotes progression to cirrhosis and predisposes to the development of hepatocellular carcinoma (HCC). Subtle inter-individual genetic variation, viral and environmental factors interact to determine the disease progression between individuals. Recently, the rs641738 Membrane Bound O-Acyltransferase Domain Containing 7 (MBOAT7) polymorphism was demonstrated to influence histological liver damage in alcoholic liver disease, nonalcoholic fatty liver disease and hepatitis C, but no data are available for CHB...
January 20, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Elizabeth A O'Hare, Rongze Yang, Laura M Yerges-Armstrong, Urmila Sreenivasan, Rebecca McFarland, Carmen C Leitch, Meredith H Wilson, Shilpa Narina, Alexis Gorden, Kathy A Ryan, Alan R Shuldiner, Steve A Farber, G Craig Wood, Christopher D Still, Glenn S Gerhard, Janet D Robishaw, Carole Sztalryd, Norann A Zaghloul
The transmembrane 6 superfamily member 2 (TM6SF2) loss-of-function variant rs58542926 is a genetic risk factor for nonalcoholic fatty liver disease and progression to fibrosis but is paradoxically associated with lower levels of hepatically derived triglyceride-rich lipoproteins. TM6SF2 is expressed predominantly in liver and small intestine, sites for triglyceride-rich lipoprotein biogenesis and export. In light of this, we hypothesized that TM6SF2 may exhibit analogous effects on both liver and intestine lipid homeostasis...
May 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Jake P Mann, Robert K Semple, Matthew J Armstrong
Improving understanding of the genetic basis of human non-alcoholic fatty liver disease (NAFLD) has the potential to facilitate risk stratification of affected patients, permit personalized treatment, and inform development of new therapeutic strategies. Animal models have been widely used to interrogate the pathophysiology of, and genetic predisposition to, NAFLD. Nevertheless, considerable interspecies differences in intermediary metabolism potentially limit the extent to which results can be extrapolated to humans...
2016: Frontiers in Endocrinology
Marcin Krawczyk, Monika Rau, Jörn M Schattenberg, Heike Bantel, Anita Pathil, Münevver Demir, Johannes Kluwe, Tobias Boettler, Frank Lammert, Andreas Geier
The PNPLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738 variants represent genetic risk factors for nonalcoholic fatty liver disease (NAFLD). Here we investigate if these polymorphisms modulate both steatosis and fibrosis in patients with NAFLD. We recruited 515 patients with NAFLD (age 16-88 years, 280 female patients). Liver biopsies were performed in 320 patients. PCR-based assays were used to genotype the PNPLA3, TM6SF2, and MBOAT7 variants. Carriers of the PNPLA3 and TM6SF2 risk alleles showed increased serum aspartate aminotransferase and alanine transaminase activities (P < 0...
January 2017: Journal of Lipid Research
Caterina Sagnelli, Marco Merli, Caterina Uberti-Foppa, Hamid Hasson, Anna Grandone, Grazia Cirillo, Stefania Salpietro, Carmine Minichini, Mario Starace, Emanuela Messina, Patrizia Morelli, Emanuele Miraglia Del Giudice, Adriano Lazzarin, Nicola Coppola, Evangelista Sagnelli
AIM: To evaluate the impact of the Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients. METHODS: The study comprised 167 consecutive patients with HIV/HCV coinfection and biopsy-proven chronic hepatitis. A pathologist graded liver fibrosis and necroinflammation using the Ishak scoring system, and steatosis using Kleiner's scoring system...
October 14, 2016: World Journal of Gastroenterology: WJG
Anna Ludovica Fracanzani, Giuseppina Pisano, Dario Consonni, Silvia Tiraboschi, Andrea Baragetti, Cristina Bertelli, Giuseppe Danilo Norata, Paola Dongiovanni, Luca Valenti, Liliana Grigore, Tatiana Tonella, Alberico Catapano, Silvia Fargion
BACKGROUND AND AIMS: Epicardial adipose tissue (EAT) has been proposed as a cardiometabolic and hepatic fibrosis risk factor in patients with non alcoholic fatty liver disease (NAFLD). Aim of this study was to evaluate the role of EAT in NAFLD by analyzing 1) the association between EAT, the other metabolic parameters and the severity of steatosis 2) the relationship between cardiovascular (cIMT, cplaques, E/A), liver (presence of NASH and significant fibrosis) damage and metabolic risk factors including EAT 3) the relationship between EAT and genetic factors strongly influencing liver steatosis...
2016: PloS One
Marcin Krawczyk, Raúl Jiménez-Agüero, José M Alustiza, José I Emparanza, María J Perugorria, Luis Bujanda, Frank Lammert, Jesús M Banales
BACKGROUND: Obesity is the major trigger of nonalcoholic fatty liver disease (NAFLD). NAFLD is further favored by the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, transmembrane 6 superfamily member 2 (TM6SF2) p.E167K, and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) rs641738 variants. OBJECTIVES: To investigate the relationship between the PNPLA3, TM6SF2, and MBOAT7 genotypes and the outcomes of bariatric surgery. SETTING: University hospital...
December 2016: Surgery for Obesity and related Diseases: Official Journal of the American Society for Bariatric Surgery
Felix Stickel, Christophe Moreno, Jochen Hampe, Marsha Y Morgan
The susceptibility to developing alcohol dependence and significant alcohol-related liver injury is determined by a number of constitutional, environmental and genetic factors, although the nature and level of interplay between them remains unclear. The familiality and heritability of alcohol dependence is well-documented but, to date, no strong candidate genes conferring increased risk have emerged, although variants in alcohol dehydrogenase and acetaldehyde dehydrogenase have been shown to confer protection, predominantly in individuals of East Asian ancestry...
January 2017: Journal of Hepatology
Tyler J Severson, Siddesh Besur, Herbert L Bonkovsky
AIM: To investigate roles of genetic polymorphisms in non-alcoholic fatty liver disease (NAFLD) onset, severity, and outcome through systematic literature review. METHODS: The authors conducted both systematic and specific searches of PubMed through December 2015 with special emphasis on more recent data (from 2012 onward) while still drawing from more historical data for background. We identified several specific genetic polymorphisms that have been most researched and, at this time, appear to have the greatest clinical significance on NAFLD and similar hepatic diseases...
August 7, 2016: World Journal of Gastroenterology: WJG
Xiaoliang Wang, Zhipeng Liu, Kai Wang, Zhaowen Wang, Xing Sun, Lin Zhong, Guilong Deng, Guohe Song, Baining Sun, Zhihai Peng, Wanqing Liu
Recent genome-wide association studies have identified that variants in or near PNPLA3, NCAN, GCKR, LYPLAL1, and TM6SF2 are significantly associated with non-alcoholic fatty liver disease (NAFLD) in multiple ethnic groups. Studies on their impact on NAFLD in Han Chinese are still limited. In this study, we examined the relevance of these variants to NAFLD in a community-based Han Chinese population and further explored their potential joint effect on NAFLD. Six single nucleotide polymorphisms (SNPs) (PNPLA3 rs738409, rs2294918, NCAN rs2228603, GCKR rs780094, LYPLAL1 rs12137855, and TM6SF2 rs58542926) previously identified in genome-wide analyses, to be associated with NAFLD were genotyped in 384 NAFLD patients and 384 age- and gender-matched healthy controls...
2016: Frontiers in Genetics
S Lallukka, H Yki-Järvinen
Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of liver disease from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is commonly associated with features of the metabolic/insulin resistance syndrome ('Metabolic/Obese NAFLD') and may therefore predict type 2 diabetes (T2DM). For this review, we searched for prospective studies examining whether NAFLD predicts T2DM, and if so, whether this occurs independently of factors such as age and obesity. These studies included NAFLD diagnosed by ultrasonography (n = 6) or liver enzymes (n = 14)...
June 2016: Best Practice & Research. Clinical Endocrinology & Metabolism
Yu-Cheng Lin, Pi-Feng Chang, Hsueh-Fang Lin, Kevin Liu, Mei-Hwei Chang, Yen-Hsuan Ni
BACKGROUND & AIMS: Autophagy has been shown to be crucial in the regulation of the intracellular lipid stores in hepatocytes. We hypothesize that immunity-related GTPase family M (IRGM) gene (an autophagy-related gene) variants confer the susceptibility to non-alcoholic fatty liver disease (NAFLD) development. METHODS: 832 obese children and adolescents aged 6-18years were recruited. NAFLD was determined by liver ultrasonography. We genotyped PNPLA3 rs738409, GCKR rs780094, TM6SF2 rs58542926, six IRGM single nucleotide polymorphisms (rs13361189, rs9637876, rs72553867, rs10065172, rs1000113, and rs11747270)...
July 12, 2016: Journal of Hepatology
Anna Viitasalo, Aino-Maija Eloranta, Mustafa Atalay, Stefano Romeo, Jussi Pihlajamäki, Timo A Lakka
BACKGROUND: We studied for the first time among children differences in plasma alanine aminotransferase (ALT) among genotypes of the rs641738 polymorphism in the MBOAT7 gene that has been associated with increased risk of nonalcoholic fatty liver disease among adults. We also investigated the associations of a genetic risk score combining information from the MBOAT7, PNPLA3, and TM6SF2 polymorphisms with plasma ALT. METHODS: We performed a 2-y follow-up study in 467 Caucasian children aged 6-9 y, genotyped the MBOAT7, PNPLA3, and TM6SF2 polymorphisms, calculated a genetic risk score from these polymorphisms (scored 0-3) and assessed plasma ALT...
November 2016: Pediatric Research
Gregor Lorbek, Žiga Urlep, Damjana Rozman
Nonalcoholic fatty liver disease (NAFLD) is a raising liver disease with increasing prevalence due to the epidemics of obesity and diabetes, with end points in cirrhosis or hepatocellular carcinoma. A multitude of genetic and metabolic perturbations, together with environmental factors, likely drive the disease. However, to date only a few genes, primarily PNPLA3 and TM6SF2, associate with NAFLD and there is no specific treatment. In this review we focus on the therapeutical aspects of NAFLD, taking into account drugs and lifestyle interventions...
July 5, 2016: Pharmacogenomics
Wasco Wruck, Nina Graffmann, Marie-Ann Kawala, James Adjaye
Considered a feature of the metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), is associated with insulin resistance, type 2 diabetes, obesity and drug toxicity. Its prevalence is estimated at about 30% in western countries mainly due to sedentary life styles and high fat diets. Genome-wide association studies have identified polymorphisms in several genes, for example, PNPLA3, and TM6SF2 which confer susceptibility to NAFLD. Here, we review recent findings in the NAFLD field with a particular focus on published transcriptomics datasets which we subject to a meta-analysis...
January 2017: Stem Cells
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