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https://www.readbyqxmd.com/read/28645116/the-additive-effects-of-the-tm6sf2-e167k-and-pnpla3-i148m-polymorphisms-on-lipid-metabolism
#1
Lizhen Chen, Shuixian Du, Linlin Lu, Zhonghua Lin, Wenwen Jin, Doudou Hu, Xiangjun Jiang, Yongning Xin, Shiying Xuan
There is a genetic susceptibility for nonalcoholic fatty liver disease (NAFLD). To examine the role of genetic factors in the disease, a Bayesian analysis was performed to model gene relationships in NAFLD pathogenesis. The Bayesian analysis indicated a potential gene interaction between the TM6SF2 and PNPLA3 genes. Next, to explore the underlying mechanism at the cellular level, we evaluated the additive effects between the TM6SF2 E167K and PNPLA3 I148M polymorphisms on lipid metabolism. Hepa 1-6 cells were transfected with a control vector or with overexpression vectors for TM6SF2/PNPLA3-wild type, TM6SF2-mutant type, PNPLA3-mutant type, or TM6SF2/PNPLA3-mutant type...
June 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28554682/liver-and-cardiovascular-damage-in-patients-with-lean-nonalcoholic-fatty-liver-disease-and-association-with-visceral-obesity
#2
Anna Ludovica Fracanzani, Salvatore Petta, Rosa Lombardi, Giuseppina Pisano, Maurizio Russello, Dario Consonni, Vito Di Marco, Calogero Cammà, Laura Mensi, Paola Dongiovanni, Luca Valenti, Antonio Craxì, Silvia Fargion
BACKGROUND & AIMS: Lean nonalcoholic fatty liver disease (NAFLD) is defined as NAFLD that develops in patients with a body mass index (BMI) less than 25 kg/m(2). We investigated the differences between lean NAFLD and NAFLD in overweight and obese persons, factors associated with the severity of liver and cardiovascular disease, and the effects of visceral obesity. METHODS: We performed a retrospective cohort study of 669 consecutive patients with biopsy-proven NAFLD seen at 3 liver centers in Italy...
May 26, 2017: Clinical Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28539357/novel-association-of-tm6sf2-rs58542926-genotype-with-increased-serum-tyrosine-levels-and-decreased-apolipoprotein-b-100-particles-in-finns
#3
Daniel Seung Kim, Anne U Jackson, Yatong K Li, Heather M Stringham, Johanna Kuusisto, Antti J Kangas, Pasi Soininen, Mika Ala-Korpela, Charles F Burant, Veikko Salomaa, Michael Boehnke, Markku Laakso, Elizabeth K Speliotes
A glutamate-to-lysine variant (rs58542926-T) in transmembrane 6 superfamily member 2 (TM6SF2) is associated with increased fatty liver disease and diabetes in conjunction with decreased cardiovascular disease risk. To identify mediators of TM6SF2 effects, we tested for associations between rs58542926-T and serum lipoprotein/metabolite measures in cross-sectional data from non-diabetic, statin-naive participants. We identified independent associations between rs58542926-T and apolipoprotein B-100 particles (B=-0...
May 24, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28464257/significant-positive-association-of-endotoxemia-with-histological-severity-in-237-patients-with-non-alcoholic-fatty-liver-disease
#4
J Pang, W Xu, X Zhang, G L-H Wong, A W-H Chan, H-Y Chan, C-H Tse, S S-T Shu, P C-L Choi, H L-Y Chan, J Yu, V W-S Wong
BACKGROUND: Patients with nonalcoholic steatohepatitis (NASH) have gut dysbiosis and intestinal bacterial overgrowth. AIM: To test the hypothesis that endotoxemia is associated with the histological severity of nonalcoholic fatty liver disease (NAFLD) and determine factors associated with endotoxemia. METHODS: The endotoxemia markers lipopolysaccharide-binding protein (LBP) and endotoxin levels were measured in 237 NAFLD patients 1 day before liver biopsy...
May 2, 2017: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28449094/hepatic-tm6sf2-overexpression-affects-cellular-apob-trafficking-plasma-lipid-levels-hepatic-steatosis-and-atherosclerosis
#5
Nicole Ehrhardt, Michael E Doche, Shuang Chen, Hui Z Mao, Meghan T Walsh, Candy Bedoya, Maha Guindi, Weidong Xiong, Joseph Ignatius Irudayam, Jahangir Iqbal, Sebastien Fuchs, Samuel W French, M Mahmood Hussain, Moshe Arditi, Vaithilingaraja Arumugaswami, Miklós Péterfy
The human TM6SF2 gene has been implicated in plasma lipoprotein metabolism, alcoholic and non-alcoholic fatty liver disease and myocardial infarction in multiple genome-wide association studies. To investigate the role of Tm6sf2 in metabolic homeostasis, we generated mice with elevated expression using adeno-associated virus (AAV)-mediated gene delivery. Hepatic overexpression of mouse Tm6sf2 resulted in phenotypes previously observed in Tm6sf2-deficient mice including reduced plasma lipid levels, diminished hepatic TG secretion and increased hepatosteatosis...
April 25, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28436986/adiposity-amplifies-the-genetic-risk-of-fatty-liver-disease-conferred-by-multiple-loci
#6
Stefan Stender, Julia Kozlitina, Børge G Nordestgaard, Anne Tybjærg-Hansen, Helen H Hobbs, Jonathan C Cohen
Complex traits arise from the interplay between genetic and environmental factors. The actions of these factors usually appear to be additive, and few compelling examples of gene-environment synergy have been documented. Here we show that adiposity significantly amplifies the effect of three sequence variants (encoding PNPLA3 p.I148M, TM6SF2 p.E167K, and GCKR p.P446L) associated with nonalcoholic fatty liver disease (NAFLD). Synergy between adiposity and genotype promoted the full spectrum of NAFLD, from steatosis to hepatic inflammation to cirrhosis...
June 2017: Nature Genetics
https://www.readbyqxmd.com/read/28434889/depletion-of-tm6sf2-disturbs-membrane-lipid-composition-and-dynamics-in-huh7-hepatoma-cells
#7
Hanna Ruhanen, P A Nidhina Haridas, Eeva-Liisa Eskelinen, Ove Eriksson, Vesa M Olkkonen, Reijo Käkelä
A polymorphism of TM6SF2 associates with hepatic lipid accumulation and reduction of triacylglycerol (TAG) secretion, but the function of the encoded protein has remained enigmatic. We studied the effect of stable TM6SF2 knock-down on the lipid content and composition, mitochondrial fatty acid oxidation and organelle structure of HuH7 hepatoma cells. Knock-down of TM6SF2 resulted in intracellular accumulation of TAGs, cholesterol esters, phosphatidylcholine (PC) and phosphatidylethanolamine. In all of these lipid classes, polyunsaturated lipid species were significantly reduced while saturated and monounsaturated species increased their proportions...
April 18, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28407767/e167k-polymorphism-of-tm6sf2-gene-affects-cell-cycle-of-hepatocellular-carcinoma-cell-hepa-1-6
#8
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
https://www.readbyqxmd.com/read/28362682/genetic-determinants-of-circulating-lipoproteins-in-nonalcoholic-fatty-liver-disease
#9
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
https://www.readbyqxmd.com/read/28303724/non-alcoholic-fatty-liver-disease-nafld-pathogenesis-classification-and-effect-on-drug-metabolizing-enzymes-and-transporters
#10
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
https://www.readbyqxmd.com/read/28242789/tm6sf2-rs58542926-variant-affects-postprandial-lipoprotein-metabolism-and-glucose-homeostasis-in-nafld
#11
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 transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (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, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis...
June 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28235613/impaired-hepatic-lipid-synthesis-from-polyunsaturated-fatty-acids-in-tm6sf2-e167k-variant-carriers-with-nafld
#12
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 22, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28109005/the-membrane-bound-o-acyltransferase-domain-containing-7-variant-rs641738-increases-inflammation-and-fibrosis-in-chronic-hepatitis-b
#13
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 interindividual genetic variation as well as viral and environmental factors interact to determine 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...
June 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28027591/tm6sf2-rs58542926-impacts-lipid-processing-in-liver-and-small-intestine
#14
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
https://www.readbyqxmd.com/read/27899914/how-useful-are-monogenic-rodent-models-for-the-study-of-human-non-alcoholic-fatty-liver-disease
#15
REVIEW
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
https://www.readbyqxmd.com/read/27836992/combined-effects-of-the-pnpla3-rs738409-tm6sf2-rs58542926-and-mboat7-rs641738-variants-on-nafld-severity-a-multicenter-biopsy-based-study
#16
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
https://www.readbyqxmd.com/read/27784963/tm6sf2-e167k-variant-predicts-severe-liver-fibrosis-for-human-immunodeficiency-hepatitis-c-virus-co-infected-patients-and-severe-steatosis-only-for-a-non-3-hepatitis-c-virus-genotype
#17
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
https://www.readbyqxmd.com/read/27627804/epicardial-adipose-tissue-eat-thickness-is-associated-with-cardiovascular-and-liver-damage-in-nonalcoholic-fatty-liver-disease
#18
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
https://www.readbyqxmd.com/read/27576208/pnpla3-p-i148m-variant-is-associated-with-greater-reduction-of-liver-fat-content-after-bariatric-surgery
#19
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
https://www.readbyqxmd.com/read/27575312/the-genetics-of-alcohol-dependence-and-alcohol-related-liver-disease
#20
REVIEW
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
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