ORCID Profile
0000-0002-4919-0592
Current Organisation
University of Utah
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Biochemistry and Cell Biology | Signal Transduction | Cell Metabolism
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Medical and Health Sciences |
Publisher: Springer Science and Business Media LLC
Date: 16-09-2019
Publisher: Elsevier BV
Date: 05-2017
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1194/JLR.C088377
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: Springer Science and Business Media LLC
Date: 21-10-2017
Abstract: Obesity, insulin resistance, type 2 diabetes mellitus and cardiovascular disease form a metabolic disease continuum that has seen a dramatic increase in prevalence in developed and developing countries over the past two decades. Dyslipidaemia resulting from hypercaloric diets is a major contributor to the pathogenesis of metabolic disease, and lipid-lowering therapies are the main therapeutic option for this group of disorders. However, the fact that dysfunctional lipid metabolism extends far beyond cholesterol and triglycerides is becoming increasingly clear. Lipidomic studies and mouse models are helping to explain the complex interactions between diet, lipid metabolism and metabolic disease. These studies are not only improving our understanding of this complex biology, but are also identifying potential therapeutic avenues to combat this growing epidemic. This Review examines what is currently known about phospholipid and sphingolipid metabolism in the setting of obesity and how metabolic pathways are being modulated for therapeutic effect.
Publisher: Oxford University Press (OUP)
Date: 08-2019
Publisher: Wiley
Date: 15-01-2019
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2202
Publisher: Elsevier BV
Date: 09-2018
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: American Society for Clinical Investigation
Date: 08-03-2018
Publisher: Springer Science and Business Media LLC
Date: 24-10-2019
Publisher: Springer Science and Business Media LLC
Date: 22-07-2022
DOI: 10.1038/S41525-022-00314-Z
Abstract: Adiponectin, encoded by ADIPOQ , is an insulin-sensitizing, anti-inflammatory, and renoprotective adipokine that activates receptors with intrinsic ceramidase activity. We identified a family harboring a 10-nucleotide deletion mutation in ADIPOQ that cosegregates with diabetes and end-stage renal disease. This mutation introduces a frameshift in exon 3, resulting in a premature termination codon that disrupts translation of adiponectin’s globular domain. Subjects with the mutation had dramatically reduced circulating adiponectin and increased long-chain ceramides levels. Functional studies suggest that the mutated protein acts as a dominant negative through its interaction with non-mutated adiponectin, decreasing circulating adiponectin levels, and correlating with metabolic disease.
Publisher: Elsevier BV
Date: 2017
Publisher: The Endocrine Society
Date: 11-03-2021
Abstract: Genome-wide association studies have identified associations between a common single nucleotide polymorphism (SNP rs267738) in CERS2, a gene that encodes a (dihydro)ceramide synthase that is involved in the biosynthesis of very-long-chain sphingolipids (eg, C20-C26) and indices of metabolic dysfunction (eg, impaired glucose homeostasis). However, the biological consequences of this mutation on enzyme activity and its causal roles in metabolic disease are unresolved. The studies described herein aimed to characterize the effects of rs267738 on CERS2 enzyme activity, sphingolipid profiles, and metabolic outcomes. We performed in-depth lipidomic and metabolic characterization of a novel CRISPR knock-in mouse modeling the rs267738 variant. In parallel, we conducted mass spectrometry-based, targeted lipidomics on 567 serum s les collected through the Utah Coronary Artery Disease study, which included 185 patients harboring 1 (n = 163) or both (n = 22) rs267738 alleles. In-silico analysis of the amino acid substitution within CERS2 caused by the rs267738 mutation suggested that rs267738 is deleterious for enzyme function. Homozygous knock-in mice had reduced liver CERS2 activity and enhanced diet-induced glucose intolerance and hepatic steatosis. However, human serum sphingolipids and a ceramide-based cardiac event risk test 1 score of cardiovascular disease were not significantly affected by rs267738 allele count. The rs267738 SNP leads to a partial loss-of-function of CERS2, which worsened metabolic parameters in knock-in mice. However, rs267738 was insufficient to effect changes in serum sphingolipid profiles in subjects from the Utah Coronary Artery Disease Study.
Publisher: Springer Science and Business Media LLC
Date: 26-03-2021
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: Oxford University Press (OUP)
Date: 26-03-2020
Abstract: Acute bed rest places older adults at risk for health complications by disrupting homeostasis in many organ systems, including the cardiovascular system. Circulating ceramides are emerging biomarkers predictive of cardiovascular and metabolic health and have recently been shown to be sensitive indices of cardiovascular (CV) risk. Therefore, the purpose of this study was to characterize the time course of changes in circulating ceramides in healthy younger and older adults after 5 days of bed rest and to determine whether short-term bed rest alters CV-related circulating ceramides. We hypothesized that circulating ceramides predictive of poor cardiometabolic outcomes would increase following 5 days of bed rest. Thirty-five healthy younger and older men and women (young: n = 13, old: n = 22) underwent 5 days of controlled bed rest. Fasting blood s les collected daily during the course of bed rest were used to measure circulating ceramides, lipoproteins, adiponectin, and fibroblast growth factor 21 (FGF21) levels. The primary findings were that circulating ceramides decreased while ceramide ratios and the cardiac event risk test 1 score were increased primarily in older adults, and these findings were independent of changes in circulating lipoprotein levels. Additionally, we found that changes in circulating adiponectin, FGF21 and the 6-minute walk test (6MW) inversely correlated with CV-related circulating ceramides after bed rest. The results of this study highlight the sensitivity of circulating ceramides to detect potential CV dysfunction that may occur with acute physical disuse in aging.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Korean Society of Lipidology and Atherosclerosis
Date: 2020
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: American Society for Clinical Investigation
Date: 27-01-2020
DOI: 10.1172/JCI131838
Publisher: Springer Science and Business Media LLC
Date: 15-05-2023
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.CMET.2016.10.002
Abstract: Adipocytes package incoming fatty acids into triglycerides and other glycerolipids, with only a fraction spilling into a parallel biosynthetic pathway that produces sphingolipids. Herein, we demonstrate that subcutaneous adipose tissue of type 2 diabetics contains considerably more sphingolipids than non-diabetic, BMI-matched counterparts. Whole-body and adipose tissue-specific inhibition/deletion of serine palmitoyltransferase (Sptlc), the first enzyme in the sphingolipid biosynthesis cascade, in mice markedly altered adipose morphology and metabolism, particularly in subcutaneous adipose tissue. The reduction in adipose sphingolipids increased brown and beige/brite adipocyte numbers, mitochondrial activity, and insulin sensitivity. The manipulation also increased numbers of anti-inflammatory M2 macrophages in the adipose bed and induced secretion of insulin-sensitizing adipokines. By comparison, deletion of serine palmitoyltransferase from macrophages had no discernible effects on metabolic homeostasis or adipose function. These data indicate that newly synthesized adipocyte sphingolipids are nutrient signals that drive changes in the adipose phenotype to influence whole-body energy expenditure and nutrient metabolism.
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 03-2019
Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 12-2021
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-07-2019
Abstract: Excess calorie intake can ultimately lead to a metabolic syndrome that interferes with fat or lipid metabolism. There are many different types of lipids, and it has been widely debated which are the true culprits underlying metabolic disorders. Chaurasia et al. report that ceramides are the major contributor to insulin resistance and fatty liver disease (see the Perspective by Kusminski and Scherer). This appears to be caused by the enzyme dihydroceramide desaturase 1 (DES1), which is normally involved in ceramide production by inserting a double bond into the backbone of the molecule. In mice fed a high-fat diet, deletion of DES1 improved glucose and lipid metabolism. Science , this issue p. 386 see also p. 319
Publisher: Cold Spring Harbor Laboratory
Date: 16-07-2021
DOI: 10.1101/2021.07.16.452686
Abstract: Fatty-acid (FA) signaling contributes to β-cell mass expansion in the face of nutrient excess, but the underlying mechanisms are poorly understood. Here we tested the hypothesis that sphingolipids, generated by the intracellular metabolism of FA, are implicated in the β-cell proliferative response to FA. Isolated rat islets were exposed to in idual FA in the presence of 16.7 mM glucose for 48 h and the contribution of the de novo sphingolipid synthesis pathway was tested using the serine palmitoyltransferase inhibitor myriocin, the sphingosine kinase (SphK) inhibitor SKI II, or adenovirus-mediated knockdown of SphK, fatty-acid-elongase-1 (ELOVL1) and acyl-CoA-binding protein (ACBP). Wistar rat were infused with glucose and the lipid emulsion ClinOleic and received SKI II by gavage. B-cell proliferation was assessed by immunochemistry or flow cytometry. Sphingolipidomic analyses were performed by LC-MS/MS. Amongst the various FA tested, only oleate increased β-cell proliferation. Myriocin, SKI II, and SphK knockdown all decreased oleate-induced β-cell proliferation. Oleate exposure did not increase the total amount of sphingolipids but led to a specific rise in 24:1 species. Knockdown of ACBP or ELOVL1 inhibited oleate-induced β-cell proliferation. We conclude that unsaturated very long-chain sphingolipids produced from the available pool of C24:1 acyl-CoA mediate oleate-induced β-cell proliferation in rats.
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.CMET.2017.12.003
Abstract: The Mayo Clinic recently introduced a diagnostic test that quantifies plasma ceramides in order to identify patients at risk of major adverse cardiac events. By comparing recent discoveries about these biomarker ceramides with the exhaustive body of literature surrounding cholesterol, Summers aims to highlight important advances and critically needed areas of investigation on this exciting class of bioactive lipids.
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: American Diabetes Association
Date: 19-05-2023
DOI: 10.2337/DBI22-0040
Publisher: American Diabetes Association
Date: 13-07-2018
DOI: 10.2337/DBI18-0018
Publisher: American Diabetes Association
Date: 22-05-2020
DOI: 10.2337/DB19-1129
Abstract: An adverse maternal in utero and lactation environment can program offspring for increased risk for metabolic disease. The aim of this study was to determine whether N-acetylcysteine (NAC), an anti-inflammatory antioxidant, attenuates programmed susceptibility to obesity and insulin resistance in offspring of mothers on a high-fat diet (HFD) during pregnancy. CD1 female mice were acutely fed a standard breeding chow or HFD. NAC was added to the drinking water (1 g/kg) of the treatment cohorts from embryonic day 0.5 until the end of lactation. NAC treatment normalized HFD-induced maternal weight gain and oxidative stress, improved the maternal lipidome, and prevented maternal leptin resistance. These favorable changes in the in utero environment normalized postnatal growth, decreased white adipose tissue (WAT) and hepatic fat, improved glucose and insulin tolerance and antioxidant capacity, reduced leptin and insulin, and increased adiponectin in HFD offspring. The lifelong metabolic improvements in the offspring were accompanied by reductions in proinflammatory gene expression in liver and WAT and increased thermogenic gene expression in brown adipose tissue. These results, for the first time, provide a mechanistic rationale for how NAC can prevent the onset of metabolic disease in the offspring of mothers who consume a typical Western HFD.
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: Elsevier BV
Date: 11-2016
Publisher: Elsevier BV
Date: 07-2022
Publisher: Elsevier BV
Date: 11-2023
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: Wiley
Date: 20-03-2016
DOI: 10.1113/JP272136
Publisher: American Association for Cancer Research (AACR)
Date: 17-08-2023
DOI: 10.1158/1055-9965.EPI-23-0278
Abstract: In iduals diagnosed with an obesity-related cancer (ORC survivors) are at an elevated risk of incident diabetes compared with cancer-free in iduals, but whether this confers survival disadvantage is unknown. We assessed the rate of incident diabetes in ORC survivors and evaluated the association of incident diabetes with all-cause and cancer-specific mortality among females with ORC in the Women's Health Initiative cohort (N = 14,651). Cox proportional hazards regression models stratified by exposure-risk periods (0–1, & –3, & –5, & –7, and & –10 years) from ORC diagnosis and time-varying exposure (diabetes) analyses were performed. Among the ORC survivors, a total of 1.3% developed diabetes within ≤1 year of follow-up and 2.5%, 2.3%, 2.3%, and 3.6% at 1–3, 3–5, 5–7, and 7–10 years of follow-up, respectively, after an ORC diagnosis. The median survival for those diagnosed with diabetes within 1-year of cancer diagnosis and those with no diabetes diagnosis in that time frame was 8.8 [95% confidence interval (CI), 7.0–14.5) years and 16.6 (95% CI, 16.1–17.0) years, respectively. New-onset compared with no diabetes as a time-varying exposure was associated with higher risk of all-cause (HR, 1.27 95% CI, 1.16–1.40) and cancer-specific (HR, 1.17 95% CI, 0.99–1.38) mortality. When stratified by exposure-risk periods, incident diabetes in ≤1 year of follow-up was associated with higher all-cause (HR, 1.76 95% CI, 1.40–2.20) and cancer-specific (HR0–1, 1.82 95% CI, 1.28–2.57) mortality, compared with no diabetes diagnosis. Incident diabetes was associated with worse cancer-specific and all-cause survival, particularly in the year after cancer diagnosis. These findings draw attention to the importance of diabetes prevention efforts among cancer survivors to improve survival outcomes.
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Start Date: 2019
End Date: 2020
Funder: National Institute of Diabetes and Digestive and Kidney Diseases
View Funded ActivityStart Date: 1997
End Date: 1999
Funder: National Institute of Diabetes and Digestive and Kidney Diseases
View Funded ActivityStart Date: 2019
End Date: 2023
Funder: National Institute of Diabetes and Digestive and Kidney Diseases
View Funded ActivityStart Date: 2001
End Date: 2006
Funder: National Institute of Diabetes and Digestive and Kidney Diseases
View Funded ActivityStart Date: 2017
End Date: 2018
Funder: National Institute of Diabetes and Digestive and Kidney Diseases
View Funded ActivityStart Date: 2008
End Date: 2009
Funder: National Institute of Diabetes and Digestive and Kidney Diseases
View Funded ActivityStart Date: 2018
End Date: 2021
Funder: National Institute of Diabetes and Digestive and Kidney Diseases
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: National Institute of Diabetes and Digestive and Kidney Diseases
View Funded ActivityStart Date: 2008
End Date: 2013
Funder: National Institute of Diabetes and Digestive and Kidney Diseases
View Funded ActivityStart Date: 2001
End Date: 2006
Funder: National Institute of Diabetes and Digestive and Kidney Diseases
View Funded ActivityStart Date: 2006
End Date: 2008
Funder: National Institute of Diabetes and Digestive and Kidney Diseases
View Funded ActivityStart Date: 2021
End Date: 12-2023
Amount: $545,000.00
Funder: Australian Research Council
View Funded Activity