A5012514266- Lipid metabolism and biosynthesis
- Peroxisome Proliferator-Activated Receptors
- Liver Disease Diagnosis and Treatment
- Endoplasmic Reticulum Stress and Disease
- Adipose Tissue and Metabolism
- Diet, Metabolism, and Disease
- Pancreatic function and diabetes
- Lipid metabolism and disorders
- Cholesterol and Lipid Metabolism
- Diabetes and associated disorders
- Hemophilia Treatment and Research
- Metabolism, Diabetes, and Cancer
- Mitochondrial Function and Pathology
- Diet and metabolism studies
- Cancer, Lipids, and Metabolism
- Lipoproteins and Cardiovascular Health
- Adipokines, Inflammation, and Metabolic Diseases
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Autophagy in Disease and Therapy
- Virus-based gene therapy research
- Protease and Inhibitor Mechanisms
- Nuclear Structure and Function
- Muscle metabolism and nutrition
- Biochemical and Molecular Research
- Phagocytosis and Immune Regulation
Discovery Institute
2019-2024
Sanford Burnham Prebys Medical Discovery Institute
2020-2024
University of California, San Diego
2021
Arthritis and Rheumatic Disease Specialties
2020
Washington University in St. Louis
2008-2018
Menlo School
2014
Akita Industrial Technology Center
2010
University of Virginia
2008
DELL (United States)
2006
Washington University Medical Center
2006
The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was targeted in mice. PGC-1alpha null (PGC-1alpha(-/-)) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. postnatal growth heart and slow-twitch skeletal muscle, organs with high mitochondrial demands, is blunted PGC-1alpha(-/-) With age, develop abnormally increased body...
Background— Cardiovascular disease is the leading cause of death among those with diabetes mellitus. Vitamin D deficiency associated an increased risk cardiovascular in this population. To determine mechanism by which vitamin mediates accelerated patients mellitus, we investigated effects active on macrophage cholesterol deposition. Methods and Results— We obtained macrophages from 76 obese, diabetic, hypertensive (25-hydroxyvitamin <80 nmol/L; group A) 4 control groups: normal (group B;...
The disaccharide trehalose blocks glucose uptake in hepatocytes and induces autophagy that prevents fatty liver disease.
Niemann-Pick Type C1 (NPC1) disease is a rare neurovisceral, cholesterol–sphingolipid lysosomal storage disorder characterized by ataxia, motor impairment, progressive intellectual decline, and dementia. The most prevalent mutation, NPC1 I1061T , encodes misfolded protein with reduced half-life caused ER-associated degradation. Therapies directed at stabilization of the mutant reduce cholesterol in fibroblasts but have not been tested vivo because lack suitable animal model. Whereas...
Regulated proinsulin biosynthesis, disulfide bond formation and ER redox homeostasis are essential to prevent Type two diabetes. In ß cells, protein isomerase A1 (PDIA1/P4HB), the most abundant oxidoreductase of over 17 members, can interact with influence maturation. Here we find Pdia1 is required for optimal insulin production under metabolic stress in vivo. cell-specific deletion young high-fat diet fed mice or aged exacerbated glucose intolerance inadequate insulinemia increased...
The assembly and secretion of hepatic very low-density lipoprotein (VLDL) plays pivotal roles in plasma lipid hemostasis the development fatty liver disease. Protein disulfide isomerase A1 (PDIA1/P4HB) functions as a molecular chaperone an oxidoreductase that is essential for protein folding endoplasmic reticulum. While PDIA1 biochemical have been extensively investigated vitro, little known about its physiological requirement vivo. subunit microsomal triglyceride transfer (MTTP) complex...
The peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha) is a highly inducible transcriptional implicated in the coordinate regulation of genes encoding enzymes involved hepatic fatty acid oxidation, oxidative phosphorylation, and gluconeogenesis. present study sought to assess effects chronic PGC-1alpha deficiency on metabolic flux through gluconeogenic, tricarboxylic cycle pathways. To this end, metabolism was assessed wild-type (WT) PGC-1alpha(-/-)...
Non-alcoholic fatty liver disease (NAFLD) is the most common in world, and it thought to be hepatic manifestation of metabolic syndrome. Excess dietary fructose causes both syndrome NAFLD rodents humans, but pathogenic mechanisms fructose-induced are poorly understood. GLUT8 (Slc2A8) a facilitative glucose transporter that highly expressed liver, heart, other oxidative tissues. We previously demonstrated female mice lacking exhibit impaired first-pass metabolism, suggesting transport into...
Intrahepatic lipid accumulation is extremely common in obese subjects and associated with the development of insulin resistance diabetes. Hepatic diacylglycerol triacylglycerol synthesis predominantly occurs through acylation glycerol-3-phosphate. However, an alternative pathway for synthesizing from monoacylglycerol acyltransferases (MGAT) could also contribute to hepatic glyceride pools. MGAT activity expression three genes encoding enzymes (MOGAT1, MOGAT2, MOGAT3) were determined liver...
Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol (DAG), a lipid that has been linked the development of hepatic insulin resistance through activation protein kinase C (PKC). The expression genes encode MGAT is induced in livers insulin-resistant human subjects with nonalcoholic fatty liver disease, but whether causal steatosis or unknown. We show Mogat1, which encodes MGAT1, and activity are also increased diet-induced obese (DIO) ob/obmice. To probe...
Depletion of Chop in pancreatic β cells optimizes insulin secretion and reduces fatty liver preclinical models.
Lipin 1 controls fatty acid metabolism in the nucleus as a transcriptional regulator and cytosol an enzyme catalyzing penultimate step phosphoglycerol triacylglyceride (TAG) synthesis. We sought to evaluate effects of lipin on hepatic TAG synthesis secretion by gain-of-function loss-of-function approaches.Rates were not impaired hepatocytes isolated from adult 1-deficient (fld) mice actually increased 14-day-old fld mice. Additionally, compared littermate controls, VLDL-TAG rates markedly...
Lipin 1 is a bifunctional intracellular protein that regulates fatty acid metabolism in the nucleus via interactions with DNA-bound transcription factors and at endoplasmic reticulum as phosphatidic phosphohydrolase enzyme (PAP-1) to catalyze penultimate step triglyceride synthesis. However, livers of 8-day-old mice lacking lipin (fld mice) exhibited normal PAP-1 activity 20-fold increase levels. We sought further analyze hepatic lipid profile these by electrospray ionization mass...
Lipin 1 is a coregulator of DNA-bound transcription factors and phosphatidic acid (PA) phosphatase (PAP) enzyme that catalyzes critical step in the synthesis glycerophospholipids. highly expressed adipocytes, constitutive loss lipin blocks adipocyte differentiation; however, effects Lpin1 deficiency differentiated adipocytes are unknown. Here we report adipocyte-specific gene recombination unexpectedly resulted expression truncated protein lacking PAP activity but retaining transcriptional...
Members of the glucose transporter (GLUT) family membrane-spanning hexose transporters are subjects intensive investigation for their potential as modifiable targets to treat or prevent obesity, metabolic syndrome, and type 2 diabetes mellitus. Mounting evidence suggests that ubiquitously expressed class III dual-specificity fructose transporter, GLUT8, has important homeostatic functions. We therefore tested hypothesis GLUT8 mediates deleterious effects chronic high-fructose diet exposure....
Lipid droplet proteins (LDPs) coat the surface of triglyceride-rich lipid droplets and regulate their formation lipolysis. We profiled hepatic LDP expression in fatty liver dystrophic (fld) mice, a unique model neonatal steatosis that predictably resolves between postnatal day 14 (P14) P17. Western blotting revealed perilipin-2/ADRP perilipin-5/OXPAT were markedly increased steatotic fld but returned to normal by However, changes perilipin-2 perilipin-5 protein content mice exaggerated...
Hemophilia A gene therapy targets hepatocytes to express B domain deleted (BDD) clotting factor VIII (FVIII) permit viral encapsidation. Since BDD is prone misfolding in the endoplasmic reticulum (ER) and ER protein followed by high-fat diet (HFD) can cause hepatocellular carcinoma (HCC), we studied how FVIII impacts HCC development using hepatocyte DNA delivery three proteins from same parental vector: (1) well-folded cytosolic dihydrofolate reductase (DHFR); (2) BDD-FVIII, which ER; (3)...
Nonphysiological truncations of apolipoprotein (apo) B-100 cause familial hypobetalipoproteinemia (FHBL) in humans and mice. An elucidation the mechanisms underlying FHBL phenotypes may provide valuable information on metabolism apo B-containing lipoproteins structure-function relationship B. To generate a faithful mouse model human FHBL, subtle mutation was introduced into B gene by targeting embryonic stem cells using homologous recombination followed removal selection marker...