A5031370408- Liver Disease Diagnosis and Treatment
- Adipose Tissue and Metabolism
- Diet, Metabolism, and Disease
- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Lipid metabolism and biosynthesis
- Regulation of Appetite and Obesity
- Diet and metabolism studies
- Peroxisome Proliferator-Activated Receptors
- Sirtuins and Resveratrol in Medicine
- Liver physiology and pathology
- Fibroblast Growth Factor Research
- Biochemical Analysis and Sensing Techniques
- Autophagy in Disease and Therapy
- Drug Transport and Resistance Mechanisms
- Cannabis and Cannabinoid Research
- Epigenetics and DNA Methylation
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Hepatocellular Carcinoma Treatment and Prognosis
- Growth Hormone and Insulin-like Growth Factors
- Kruppel-like factors research
- Amino Acid Enzymes and Metabolism
- Endoplasmic Reticulum Stress and Disease
- Diabetes Treatment and Management
- Adipokines, Inflammation, and Metabolic Diseases
Takeda (United States)
2016-2023
Pfizer (United States)
2013-2021
Takeda (Japan)
2019-2021
University of Montana
2016
University of California, San Diego
2016
Yale University
2008-2014
Howard Hughes Medical Institute
2008-2013
Monash University
2010
Insulin resistance is associated with nonalcoholic fatty liver disease (NAFLD) and a major factor in the pathogenesis of type 2 diabetes. The development hepatic insulin has been ascribed to multiple causes, including inflammation, endoplasmic reticulum (ER) stress, accumulation hepatocellular lipids animal models NAFLD. However, it unknown whether these same cellular mechanisms link steatosis humans. To examine that resistance, we comprehensively assessed each pathways by using flash-frozen...
Abstract CD36/FAT (fatty acid translocase) is associated with human and murine nonalcoholic fatty liver disease, but it has been unclear whether simply a marker or directly contributes to disease pathogenesis. Mice hepatocyte-specific deletion of Janus kinase 2 (JAK2L mice) have increased circulating free acids (FAs), dramatically hepatic CD36 expression profound liver. To investigate the role elevated in development liver, we studied two models steatosis, genetic model high-fat diet...
Ghrelin targets the hypothalamus to regulate food intake and adiposity. Endogenous ghrelin receptors [growth hormone secretagogue receptor (GHSR)] are also present in extrahypothalamic sites where they promote circuit activity associated with learning memory, reward seeking behavior. Here, we show that substantia nigra pars compacta (SNpc), a brain region dopamine (DA) cell degeneration leads Parkinson's disease (PD), expresses GHSR. binds SNpc cells, electrically activates DA neurons,...
OBJECTIVE Macrophage recruitment to adipose tissue is a reproducible feature of obesity. However, the events that result in chemokine production and macrophage during states energetic excess are not clear. Sirtuin 1 (SirT1) an essential nutrient-sensing histone deacetylase, which increased by caloric restriction reduced overfeeding. We discovered SirT1 depletion causes anorexia stimulating inflammatory factors white thus posit decreases link overnutrition inflammation. RESEARCH DESIGN AND...
Hepatic gluconeogenesis is a major contributing factor to hyperglycemia in the fasting and postprandial states type 2 diabetes mellitus (T2DM). Because Sirtuin 1 (SirT1) induces hepatic during through induction of phosphoenolpyruvate carboxylase kinase (PEPCK), fructose-1,6-bisphosphatase (FBPase), glucose-6-phosphatase (G6Pase) gene transcription, we hypothesized that reducing SirT1, by using an antisense oligonucleotide (ASO), would decrease rat model T2DM. SirT1 ASO lowered both glucose...
Recent studies suggest that excess dietary fructose contributes to metabolic dysfunction by promoting insulin resistance, de novo lipogenesis (DNL), and hepatic steatosis, thereby increasing the risk of obesity, type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH), related comorbidities. Whether this is driven calories contained in or whether catabolism itself uniquely pathogenic remains controversial. We sought test a small molecule inhibitor primary metabolizing enzyme...
Liver-specific thyroid hormone receptor-β (TRβ)-specific agonists are potent lipid-lowering drugs that also hold promise for treating nonalcoholic fatty liver disease and hepatic insulin resistance. We investigated the effect of two TRβ (GC-1 KB-2115) in high-fat-fed male Sprague-Dawley rats treated 10 days. GC-1 treatment reduced triglyceride content by 75%, but developed fasting hyperglycemia hyperinsulinemia, attributable to increased endogenous glucose production (EGP) diminished...
Genome-wide array studies have associated the patatin-like phospholipase domain-containing 3 (PNPLA3) gene polymorphisms with hepatic steatosis. However, it is unclear whether PNPLA3 functions as a lipase or lipogenic enzyme and involved in pathogenesis of insulin resistance. To address these questions we treated high-fat-fed rats specific antisense oligonucleotides to decrease adipose pnpla3 expression. Reducing expression prevented steatosis, which could be attributed decreased fatty acid...
By 2030, nearly half of Americans will have nonalcoholic fatty liver disease. In part, this epidemic is fueled by the increasing consumption caloric sweeteners coupled with an innate capacity to convert sugar into fat via hepatic de novo lipogenesis. addition serving as substrates, monosaccharides also increase expression key enzymes involved in lipogenesis carbohydrate response element-binding protein (ChREBP). To determine whether ChREBP a potential therapeutic target, we decreased...
The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification the pyrrolidine amide group for a significant LipE improvement, (2) insertion sp(3)-hybridized carbon center in core molecule simultaneous improvement N-glucuronidation metabolic liability off-target pharmacology. candidate 9...
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...
Citrate is a key regulatory metabolic intermediate as it facilitates the integration of glycolysis and lipid synthesis pathways. Inhibition hepatic extracellular citrate uptake, by blocking sodium-coupled transporter (NaCT or SLC13A5), has been suggested potential therapeutic approach to treat disorders. NaCT transports from blood into cell coupled transport sodium ions. The studies herein report identification characterization novel small dicarboxylate molecule (compound 2) capable...
Fibroblast growth factor 21 (FGF21) shows great potential for the treatment of obesity and type 2 diabetes, as its long-acting analogue reduces body weight improves lipid profiles participants in clinical studies; however, intracellular mechanisms mediating these effects are poorly understood. AMP-activated protein kinase (AMPK) is an important energy sensor cell a molecular target anti-diabetic medications. This work examined role AMPK glucose lipid-lowering FGF21. Inducible adipocyte β1β2...
Palatable foods (fat and sweet) induce hyperphagia, facilitate the development of obesity. Whether how overnutrition increases appetite through adipose-to-brain axis is unclear. O-linked beta-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) couples nutrient cues to O-GlcNAcylation intracellular proteins at serine/threonine residues. Chronic dysregulation O-GlcNAc signaling contributes metabolic diseases. Here we show that adipocyte OGT essential for high fat diet-induced but dispensable...
Increasing evidence highlights dietary fructose as a major driver of non-alcoholic fatty liver disease (NAFLD) pathogenesis, the majority which is cleared on first pass through hepatic circulation by enzymatic phosphorylation to fructose-1-phosphate via ketohexokinase (KHK) enzyme. Without current approved therapy, management emphasises lifestyle interventions, but few patients adhere such strategies. New targeted therapies are urgently required.We have used unique combination human...