A5008887250- Liver Disease Diagnosis and Treatment
- Endoplasmic Reticulum Stress and Disease
- Lipid metabolism and biosynthesis
- Hepatitis C virus research
- Diet, Metabolism, and Disease
- Hepatitis B Virus Studies
- Genetic Associations and Epidemiology
- Peroxisome Proliferator-Activated Receptors
- Pancreatic function and diabetes
- Drug Transport and Resistance Mechanisms
- Liver Diseases and Immunity
- Cholesterol and Lipid Metabolism
- Cancer, Lipids, and Metabolism
- RNA modifications and cancer
Regeneron (United States)
2022-2024
The University of Texas Southwestern Medical Center
2014-2021
Pauls Stradiņš Clinical University Hospital
2005
A sequence polymorphism (rs738409, I148M) in patatin‐like phospholipid domain containing protein 3 ( PNPLA3 ) is strongly associated with nonalcoholic fatty liver disease (NAFLD), but the mechanistic basis for this association remains enigmatic. Neither ablation nor overexpression of wild‐type affects fat content mice, whereas hepatic human 148M transgene causes steatosis. To determine whether allele accumulation when expressed at physiological levels, we introduced a methionine codon...
Significance A sequence variant (I148M) in PNPLA3 is a major genetic risk factor for nonalcoholic fatty liver disease. Previously, we showed that PNPLA3(148M) evades ubiquitylation-mediated degradation and accumulates to high levels on lipid droplets (LDs). Here address how this accumulation related steatosis. We generated an active, ubiquitylation-resistant isoform accumulated LDs increased hepatic triglyceride when expressed livers of mice. Conversely, depletion resolved the excess fat...
A sequence variation (I148M) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is strongly associated with fatty liver disease, but the underlying mechanism remains obscure. In this study, we used knock-in (KI) mice (Pnpla3148M/M ) to examine responsible for accumulation of triglyceride (TG) and PNPLA3 hepatic lipid droplets (LDs). No differences were found between Pnpla3148M/M Pnpla3+/+ TG synthesis, utilization, or secretion. These results are consistent being caused by...
Exome sequencing in hundreds of thousands persons may enable the identification rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for discovery new therapeutic targets.
Substitution of lysine for glutamic acid at residu 167 in Transmembrane 6 superfamily member 2 (TM6SF2) is associated with fatty liver disease and reduced plasma lipid levels. Tm6sf2-/- mice replicate the human phenotype but were not suitable detailed mechanistic studies. As an alternative model, we generated rats to determine subcellular location function TM6SF2.Two lines established using gene editing. Lipids from tissues newly secreted very low density lipoproteins (VLDLs) quantified...
Genetic variation at rs4240624 on chromosome 8 is associated with an attenuated signal hepatic computerized tomography, which has been attributed to changes in fat. The closest coding gene rs4240624, PPP1R3B, encodes a protein that promotes glycogen synthesis. Here, we performed studies determine whether the x-ray attenuation due differences or triglyceride content (HTGC). A sequence variant complete linkage disequilibrium rs4841132, was genotyped Dallas Heart Study (DHS), Liver Study, and...
Recent human genome-wide association studies have identified common missense variants in MARC1 , p.Ala165Thr and p.Met187Lys, associated with lower hepatic fat, reduction liver enzymes protection from most causes of cirrhosis. Using an exome-wide study we recapitulated earlier p.Met187Lys findings 540,000 individuals five ancestry groups. We also discovered novel rare putative loss function a phenotype similar to p.Ala165Thr/p.Met187Lys variants. In vitro recombinant protein revealed...
The incidence of genome variants hepatitis B and C viruses among 38 long-term (2–15 years) immunosuppressed patients after renal transplantation 10 undergoing dialysis was investigated. Twelve had only HBV infection, 9 HCV infection 14 were co-infected. Regions corresponding to the X/EnII/BCP, preC/C, preS/S core sequenced for molecular characterization genomes. Fifty-seven percent DNA isolates belonged genotype D 42% A, whereas 77% RNA 1b 17% 3a. One sample (6%) 2c. Detailed analysis...
Non‐alcoholic fatty liver disease (NAFLD) is a burgeoning health problem in Western countries. Population‐based surveys indicate that one out of every three adults the United States has excess fat (hepatic steatosis), first stage disease. Despite clinical importance NAFLD, major questions remain regarding its etiology. As step towards elucidating pathophysiology this disorder, we screened individuals population‐based study, Dallas Heart Study (DHS) for DNA sequence variations associated with...
Abstract Background A missense variant in Transmembrane 6 Superfamily Member 2 [TM6SF2 (E167K)] is associated with reduced plasma lipid levels and protection from coronary atherosclerosis. The substitution of lysine for glutamate at residue 167 a marked decrease TM6SF2 protein expression, consistent loss-of-function mutation. However the biological role not known, mechanism(s) responsible hypolipidemia mutation gene has been fully defined. To elucidate pathological mechanism deficiency, we...
Background: A missense variant (E167K) in Transmembrane 6 Superfamily Member 2 (TM6SF2) is associated with lower plasma lipid levels and protection from coronary artery disease. Inactivation of Tm6sf2 mice results increased hepatic triglyceride (TG) content a reduced rate secretion very low-density lipoprotein (VLDL)-TG, but not VLDL-Apolipoprotein B (ApoB). To determine the mechanism responsible for hypolipidemic effect inactivation, we performed liver perfusion electron microscopy studies...