Publications by authors named "William L Holland"

87 Publications

Ceramides and other sphingolipids as drivers of cardiovascular disease.

Nat Rev Cardiol 2021 Mar 26. Epub 2021 Mar 26.

Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.

Increases in calorie consumption and sedentary lifestyles are fuelling a global pandemic of cardiometabolic diseases, including coronary artery disease, diabetes mellitus, cardiomyopathy and heart failure. These lifestyle factors, when combined with genetic predispositions, increase the levels of circulating lipids, which can accumulate in non-adipose tissues, including blood vessel walls and the heart. The metabolism of these lipids produces bioactive intermediates that disrupt cellular function and survival. A compelling body of evidence suggests that sphingolipids, such as ceramides, account for much of the tissue damage in these cardiometabolic diseases. In humans, serum ceramide levels are proving to be accurate biomarkers of adverse cardiovascular disease outcomes. In mice and rats, pharmacological inhibition or depletion of enzymes driving de novo ceramide synthesis prevents the development of diabetes, atherosclerosis, hypertension and heart failure. In cultured cells and isolated tissues, ceramides perturb mitochondrial function, block fuel usage, disrupt vasodilatation and promote apoptosis. In this Review, we discuss the body of literature suggesting that ceramides are drivers - and not merely passengers - on the road to cardiovascular disease. Moreover, we explore the feasibility of therapeutic strategies to lower ceramide levels to improve cardiovascular health.
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http://dx.doi.org/10.1038/s41569-021-00536-1DOI Listing
March 2021

Characterizing a common CERS2 polymorphism in a mouse model of metabolic disease and in subjects from the Utah CAD Study.

J Clin Endocrinol Metab 2021 Mar 11. Epub 2021 Mar 11.

Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, USA.

Context: 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 involved in the biosynthesis of very-long chain sphingolipids (e.g. C20-C26) - and indices of metabolic dysfunction (e.g. impaired glucose homeostasis). However, the biological consequences of this mutation on enzyme activity and its causal roles in metabolic disease are unresolved.

Objective: The studies described herein aimed to characterize the effects of rs267738 on CERS2 enzyme activity, sphingolipid profiles, and metabolic outcomes.

Design: 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 samples collected through the Utah Coronary Artery Disease study, which included 185 patients harboring one (n = 163) or both (n = 22) rs267738 alleles.

Results: 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 CERT1 risk score of cardiovascular disease were not significantly affected by rs267738 allele count.

Conclusions: 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.
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http://dx.doi.org/10.1210/clinem/dgab155DOI Listing
March 2021

Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets.

Proc Natl Acad Sci U S A 2021 Mar;118(9)

Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549;

We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted β-cell survival and enhanced the recovery of insulin islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of β-cell apoptosis which allows for robust assessment of β-cell regeneration following caspase-8-induced diabetes, Ab-4 drove a 6.7-fold increase in β-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by α-cell-to-β-cell conversion. Following hyperglycemic onset in nonobese diabetic (NOD) mice, Ab-4 treatment promoted improvements in C-peptide levels and insulin islet mass was dramatically increased. Lastly, diabetic mice receiving human islet xenografts showed stable improvements in glycemic control and increased human insulin secretion.
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http://dx.doi.org/10.1073/pnas.2022142118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936318PMC
March 2021

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle.

J Clin Invest 2021 Feb 16. Epub 2021 Feb 16.

Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States of America.

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from lean insulin-sensitive (LN) and obese insulin-resistant (OB) individuals revealed several species of lysophospholipids (lyso-PL) that were differentially-abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lyso-PC/PC, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.
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http://dx.doi.org/10.1172/JCI135963DOI Listing
February 2021

Ceramides are necessary and sufficient for diet-induced impairment of thermogenic adipocytes.

Mol Metab 2021 Mar 19;45:101145. Epub 2020 Dec 19.

Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT, USA.

Objective: Aging and weight gain lead to a decline in brown and beige adipocyte functionality that exacerbates obesity and insulin resistance. We sought to determine whether sphingolipids, such as ceramides, a class of lipid metabolites that accumulate in aging and overnutrition, are sufficient or necessary for the metabolic impairment of these thermogenic adipocytes.

Methods: We generated new mouse models allowing for the conditional ablation of genes required for ceramide synthesis (i.e., serine palmitoyltransferase subunit 2, Sptlc2) or degradation (i.e., acid ceramidase 1, Asah1) from mature, thermogenic adipocytes (i.e., from cells expressing uncoupling protein-1). Mice underwent a comprehensive suite of phenotyping protocols to assess energy expenditure and glucose and lipid homeostasis. Complementary studies were conducted in primary brown adipocytes to dissect the mechanisms controlling ceramide synthesis or action.

Results: Depletion of Sptlc2 increased energy expenditure, improved glucose homeostasis, and prevented diet-induced obesity. Conversely, depletion of Asah1 led to ceramide accumulation, diminution of energy expenditure, and exacerbation of insulin resistance and obesity. Mechanistically, ceramides slowed lipolysis, inhibited glucose uptake, and decreased mitochondrial respiration. Moreover, β-adrenergic receptor agonists, which activate thermogenesis in brown adipocytes, decreased transcription of enzymes required for ceramide synthesis.

Conclusions: These studies support our hypothesis that ceramides are necessary and sufficient for the impairment in thermogenic adipocyte function that accompanies obesity. Moreover, they suggest that implementation of therapeutic strategies to block ceramide synthesis in thermogenic adipocytes may serve as a means of improving adipose health and combating obesity and cardiometabolic disease.
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http://dx.doi.org/10.1016/j.molmet.2020.101145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807150PMC
March 2021

The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure.

Cell Metab 2021 Mar 16;33(3):629-648.e10. Epub 2020 Dec 16.

Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA; U.T.A.H. (Utah Transplant Affiliated Hospitals) Cardiac Transplant Program: University of Utah Healthcare and School of Medicine, Intermountain Medical Center, Salt Lake VA (Veterans Affairs) Health Care System, Salt Lake City, UT, USA. Electronic address:

The metabolic rewiring of cardiomyocytes is a widely accepted hallmark of heart failure (HF). These metabolic changes include a decrease in mitochondrial pyruvate oxidation and an increased export of lactate. We identify the mitochondrial pyruvate carrier (MPC) and the cellular lactate exporter monocarboxylate transporter 4 (MCT4) as pivotal nodes in this metabolic axis. We observed that cardiac assist device-induced myocardial recovery in chronic HF patients was coincident with increased myocardial expression of the MPC. Moreover, the genetic ablation of the MPC in cultured cardiomyocytes and in adult murine hearts was sufficient to induce hypertrophy and HF. Conversely, MPC overexpression attenuated drug-induced hypertrophy in a cell-autonomous manner. We also introduced a novel, highly potent MCT4 inhibitor that mitigated hypertrophy in cultured cardiomyocytes and in mice. Together, we find that alteration of the pyruvate-lactate axis is a fundamental and early feature of cardiac hypertrophy and failure.
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http://dx.doi.org/10.1016/j.cmet.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933116PMC
March 2021

Metabolic Messengers: ceramides.

Nat Metab 2019 11 24;1(11):1051-1058. Epub 2019 Oct 24.

Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Center, University of Utah, Salt Lake City, UT, USA.

Ceramides are products of metabolism that accumulate in individuals with obesity or dyslipidaemia and alter cellular processes in response to fuel surplus. Their actions, when prolonged, elicit the tissue dysfunction that underlies diabetes and heart disease. Here, we review the history of research on these enigmatic molecules, exploring their discovery and mechanisms of action, the evolutionary pressures that have given them their unique attributes and the potential of ceramide-reduction therapies as treatments for cardiometabolic disease.
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http://dx.doi.org/10.1038/s42255-019-0134-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549391PMC
November 2019

Depletion of adipocyte sphingosine kinase 1 leads to cell hypertrophy, impaired lipolysis, and nonalcoholic fatty liver disease.

J Lipid Res 2020 10 20;61(10):1328-1340. Epub 2020 Jul 20.

Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA

Sphingolipids have become established participants in the pathogenesis of obesity and its associated maladies. Sphingosine kinase 1 (SPHK1), which generates S1P, has been shown to increase in liver and adipose of obese humans and mice and to regulate inflammation in hepatocytes and adipose tissue, insulin resistance, and systemic inflammation in mouse models of obesity. Previous studies by us and others have demonstrated that global sphingosine kinase 1 KO mice are protected from diet-induced obesity, insulin resistance, systemic inflammation, and NAFLD, suggesting that SPHK1 may mediate pathological outcomes of obesity. As adipose tissue dysfunction has gained recognition as a central instigator of obesity-induced metabolic disease, we hypothesized that SPHK1 intrinsic to adipocytes may contribute to HFD-induced metabolic pathology. To test this, we depleted from adipocytes in mice (SK1) and placed them on a HFD. In contrast to our initial hypothesis, SK1 mice displayed greater weight gain on HFD and exacerbated impairment in glucose clearance. Pro-inflammatory cytokines and neutrophil content of adipose tissue were similar, as were levels of circulating leptin and adiponectin. However, SPHK1-null adipocytes were hypertrophied and had lower basal lipolytic activity. Interestingly, hepatocyte triacylglycerol accumulation and expression of pro-inflammatory cytokines and collagen 1a1 were exacerbated in SK1 mice on a HFD, implicating a specific role for adipocyte SPHK1 in adipocyte function and inter-organ cross-talk that maintains overall metabolic homeostasis in obesity. Thus, SPHK1 serves a previously unidentified essential homeostatic role in adipocytes that protects from obesity-associated pathology. These findings may have implications for pharmacological targeting of the SPHK1/S1P signaling axis.
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http://dx.doi.org/10.1194/jlr.RA120000875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529052PMC
October 2020

Phospholipid methylation regulates muscle metabolic rate through Ca transport efficiency.

Nat Metab 2019 09 16;1(9):876-885. Epub 2019 Sep 16.

Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, UT, USA.

The biophysical environment of membrane phospholipids affects structure, function, and stability of membrane-bound proteins. Obesity can disrupt membrane lipids, and in particular, alter the activity of sarco/endoplasmic reticulum (ER/SR) Ca-ATPase (SERCA) to affect cellular metabolism. Recent evidence suggests that transport efficiency (Ca uptake / ATP hydrolysis) of skeletal muscle SERCA can be uncoupled to increase energy expenditure and protect mice from diet-induced obesity. In isolated SR vesicles, membrane phospholipid composition is known to modulate SERCA efficiency. Here we show that skeletal muscle SR phospholipids can be altered to decrease SERCA efficiency and increase whole-body metabolic rate. The absence of skeletal muscle phosphatidylethanolamine (PE) methyltransferase (PEMT) promotes an increase in skeletal muscle and whole-body metabolic rate to protect mice from diet-induced obesity. The elevation in metabolic rate is caused by a decrease in SERCA Ca-transport efficiency, whereas mitochondrial uncoupling is unaffected. Our findings support the hypothesis that skeletal muscle energy efficiency can be reduced to promote protection from obesity.
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http://dx.doi.org/10.1038/s42255-019-0111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218817PMC
September 2019

Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice.

J Lipid Res 2020 07 12;61(7):983-994. Epub 2020 May 12.

Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA. Electronic address:

Alcohol's impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis, and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp. Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet (LD) accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and LD compartments. We additionally demonstrate that hepatic ceramide reduction prevents alcohol's inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri- LD ASAH expression in human ALD. Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD.
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http://dx.doi.org/10.1194/jlr.RA119000446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328039PMC
July 2020

Ceramide Biomarkers Predictive of Cardiovascular Disease Risk Increase in Healthy Older Adults After Bed Rest.

J Gerontol A Biol Sci Med Sci 2020 09;75(9):1663-1670

Department of Physical Therapy and Athletic Training, University of Utah, Salt Lake City.

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 samples 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.
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http://dx.doi.org/10.1093/gerona/glaa072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494040PMC
September 2020

Novel four-disulfide insulin analog with high aggregation stability and potency.

Chem Sci 2020 Jan 5;11(1):195-200. Epub 2019 Nov 5.

Department of Biochemistry , University of Utah , Salt Lake City UT 84112 , USA . Email: ; Email:

Although insulin was first purified and used therapeutically almost a century ago, there is still a need to improve therapeutic efficacy and patient convenience. A key challenge is the requirement for refrigeration to avoid inactivation of insulin by aggregation/fibrillation. Here, in an effort to mitigate this problem, we introduced a 4 disulfide bond between a C-terminal extended insulin A chain and residues near the C-terminus of the B chain. Insulin activity was retained by an analog with an additional disulfide bond between residues A22 and B22, while other linkages tested resulted in much reduced potency. Furthermore, the A22-B22 analog maintains the native insulin tertiary structure as demonstrated by X-ray crystal structure determination. We further demonstrate that this four-disulfide analog has similar potency in mice compared to native insulin and demonstrates higher aggregation stability. In conclusion, we have discovered a novel four-disulfide insulin analog with high aggregation stability and potency.
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http://dx.doi.org/10.1039/c9sc04555dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012051PMC
January 2020

A Novel Model of Diabetic Complications: Adipocyte Mitochondrial Dysfunction Triggers Massive β-Cell Hyperplasia.

Diabetes 2020 03 27;69(3):313-330. Epub 2019 Dec 27.

Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX

Obesity-associated type 2 diabetes mellitus (T2DM) entails insulin resistance and loss of β-cell mass. Adipose tissue mitochondrial dysfunction is emerging as a key component in the etiology of T2DM. Identifying approaches to preserve mitochondrial function, adipose tissue integrity, and β-cell mass during obesity is a major challenge. Mitochondrial ferritin (FtMT) is a mitochondrial matrix protein that chelates iron. We sought to determine whether perturbation of adipocyte mitochondria influences energy metabolism during obesity. We used an adipocyte-specific doxycycline-inducible mouse model of FtMT overexpression (FtMT-Adip mice). During a dietary challenge, FtMT-Adip mice are leaner but exhibit glucose intolerance, low adiponectin levels, increased reactive oxygen species damage, and elevated GDF15 and FGF21 levels, indicating metabolically dysfunctional fat. Paradoxically, despite harboring highly dysfunctional fat, transgenic mice display massive β-cell hyperplasia, reflecting a beneficial mitochondria-induced fat-to-pancreas interorgan signaling axis. This identifies the unique and critical impact that adipocyte mitochondrial dysfunction has on increasing β-cell mass during obesity-related insulin resistance.
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http://dx.doi.org/10.2337/db19-0327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034182PMC
March 2020

Synthesis and Characterization of an A6-A11 Methylene Thioacetal Human Insulin Analogue with Enhanced Stability.

J Med Chem 2019 12 13;62(24):11437-11443. Epub 2019 Dec 13.

Department of Biochemistry , University of Utah , Salt Lake City , Utah 84112 , United States.

Insulin has been a life-saving drug for millions of people with diabetes. However, several challenges exist which limit therapeutic benefits and reduce patient convenience. One key challenge is the fibrillation propensity, which necessitates refrigeration for storage. To address this limitation, we chemically synthesized and evaluated a methylene thioacetal human insulin analogue (SCS-Ins). The synthesized SCS-Ins showed enhanced serum stability and aggregation resistance while retaining bioactivity compared with native insulin.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217704PMC
December 2019

Machine learning reveals serum sphingolipids as cholesterol-independent biomarkers of coronary artery disease.

J Clin Invest 2020 03;130(3):1363-1376

Department of Nutrition and Integrative Physiology and.

BACKGROUNDCeramides are sphingolipids that play causative roles in diabetes and heart disease, with their serum levels measured clinically as biomarkers of cardiovascular disease (CVD).METHODSWe performed targeted lipidomics on serum samples from individuals with familial coronary artery disease (CAD) (n = 462) and population-based controls (n = 212) to explore the relationship between serum sphingolipids and CAD, using unbiased machine learning to identify sphingolipid species positively associated with CAD.RESULTSNearly every sphingolipid measured (n = 30 of 32) was significantly elevated in subjects with CAD compared with measurements in population controls. We generated a novel sphingolipid-inclusive CAD risk score, termed SIC, that demarcates patients with CAD independently and more effectively than conventional clinical CVD biomarkers including serum LDL cholesterol and triglycerides. This new metric comprises several minor lipids that likely serve as measures of flux through the ceramide biosynthesis pathway rather than the abundant deleterious ceramide species that are included in other ceramide-based scores.CONCLUSIONThis study validates serum ceramides as candidate biomarkers of CVD and suggests that comprehensive sphingolipid panels should be considered as measures of CVD.FUNDINGThe NIH (DK112826, DK108833, DK115824, DK116888, and DK116450); the Juvenile Diabetes Research Foundation (JDRF 3-SRA-2019-768-A-B); the American Diabetes Association; the American Heart Association; the Margolis Foundation; the National Cancer Institute, NIH (5R00CA218694-03); and the Huntsman Cancer Institute Cancer Center Support Grant (P30CA040214).
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http://dx.doi.org/10.1172/JCI131838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269567PMC
March 2020

Identification of a Paracrine Signaling Mechanism Linking CD34 Progenitors to the Regulation of Visceral Fat Expansion and Remodeling.

Cell Rep 2019 10;29(2):270-282.e5

Department of Nutrition and Integrative Physiology and Program in Molecular Medicine, University of Utah College of Health, Salt Lake City, UT 84112, USA. Electronic address:

Accumulation of visceral (VIS) is a predictor of metabolic disorders and insulin resistance. This is due in part to the limited capacity of VIS fat to buffer lipids allowing them to deposit in insulin-sensitive tissues. Mechanisms underlying selective hypertrophic growth and tissue remodeling properties of VIS fat are not well understood. We identified subsets of adipose progenitors (APs) unique to VIS fat with differential Cd34 expression and adipogenic capacity. VIS low (Cd34 low) APs are adipogenic, whereas VIS high (Cd34 high) APs are not. Furthermore, VIS high APs inhibit adipogenic differentiation of SUB and VIS low APs in vitro through the secretion of soluble inhibitory factor(s). The number of VIS high APs increased with adipose tissue expansion, and their abundance in vivo caused hypertrophic growth, fibrosis, inflammation, and metabolic dysfunction. This study unveils the presence of APs unique to VIS fat involved in the paracrine regulation of adipogenesis and tissue remodeling.
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http://dx.doi.org/10.1016/j.celrep.2019.08.092DOI Listing
October 2019

FOXN3 controls liver glucose metabolism by regulating gluconeogenic substrate selection.

Physiol Rep 2019 09;7(18):e14238

University of Utah Molecular Medicine Program, Salt Lake City, Utah.

The FOXN3 gene locus is associated with fasting blood glucose levels in non-diabetic human population genetic studies. The blood glucose-modifying variation within this gene regulates the abundance of both FOXN3 protein and transcript in primary human hepatocytes, with the hyperglycemia risk allele causing increases in both FOXN3 protein and transcript. Using transgenic and knock-out zebrafish models, we showed previously that FOXN3 is a transcriptional repressor that regulates fasting blood glucose by altering liver gene expression of MYC, a  master transcriptional regulator of glucose utilization, and by modulating pancreatic α cell mass and function through an unknown mechanism. Since homozygous Foxn3 null mice die perinatally, and heterozygous carries of the null allele are smaller than wild-type siblings, we examine the metabolic effects of decreasing mouse liver Foxn3 expression in adult life, performing dynamic endocrine tests not feasible in adult zebrafish. Fasting glucose, glucagon, and insulin; and dynamic responses to glucose, insulin, pyruvate, glutamine, and glucagon were measured. Gluconeogenic and amino acid catabolic gene expression was examined in livers, as well. Knocking down liver Foxn3 expression via transduction with adeno-associated virus serotype 8 particles encoding a short hairpin RNA targeting Fonx3 decreases fasting glucose and increases Myc expression, without altering fasting glucagon or fasting insulin. Liver Foxn3 knock-down confers increases glucose tolerance, has no effect on insulin tolerance or response to glucagon challenge, blunts pyruvate and glutamine tolerance, and modulates expression of amino acid transporters and catabolic enzymes. We conclude that liver Foxn3 regulates substrate selection for gluconeogenesis.
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http://dx.doi.org/10.14814/phy2.14238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759504PMC
September 2019

Risky lipids: refining the ceramide score that measures cardiovascular health.

Eur Heart J 2020 01;41(3):381-382

Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.

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http://dx.doi.org/10.1093/eurheartj/ehz525DOI Listing
January 2020

Targeting a ceramide double bond improves insulin resistance and hepatic steatosis.

Science 2019 07 4;365(6451):386-392. Epub 2019 Jul 4.

Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT 84112, USA.

Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase 1 (DES1), which normally inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals or tissue-specific deletion in the liver and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or obesogenic diets. Mechanistic studies revealed ceramide actions that promoted lipid uptake and storage and impaired glucose utilization, none of which could be recapitulated by (dihydro)ceramides that lacked the critical double bond. These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and metabolic disorders.
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http://dx.doi.org/10.1126/science.aav3722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787918PMC
July 2019

Listen to your heart when ceramide's calling for higher glucose.

EBioMedicine 2019 Mar 7;41:3-4. Epub 2019 Feb 7.

Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT 84112, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2019.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441998PMC
March 2019

PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice.

Proc Natl Acad Sci U S A 2018 11 12;115(48):12102-12111. Epub 2018 Nov 12.

Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390;

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation and is the target for the insulin-sensitizing thiazolidinedione (TZD) drugs used to treat type 2 diabetes. In cell-based in vitro studies, the transcriptional activity of PPARγ is inhibited by covalent attachment of small ubiquitin-related modifier (SUMOylation) at K107 in its N terminus. However, whether this posttranslational modification is relevant in vivo remains unclear. Here, using mice homozygous for a mutation (K107R) that prevents SUMOylation at this position, we demonstrate that PPARγ is SUMOylated at K107 in white adipose tissue. We further show that in the context of diet-induced obesity PPARγ-K107R-mutant mice have enhanced insulin sensitivity without the corresponding increase in adiposity that typically accompanies PPARγ activation by TZDs. Accordingly, the PPARγ-K107R mutation was weaker than TZD treatment in stimulating adipocyte differentiation in vitro. Moreover, we found that both the basal and TZD-dependent transcriptomes of inguinal and epididymal white adipose tissue depots were markedly altered in the K107R-mutant mice. We conclude that PPARγ SUMOylation at K107 is physiologically relevant and may serve as a pharmacologic target for uncoupling PPARγ's beneficial insulin-sensitizing effect from its adverse effect of weight gain.
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http://dx.doi.org/10.1073/pnas.1814522115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275522PMC
November 2018

Strong Heart, Low Ceramides.

Diabetes 2018 08;67(8):1457-1460

Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT

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http://dx.doi.org/10.2337/dbi18-0018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054437PMC
August 2018

A Hepatocyte FOXN3-α Cell Glucagon Axis Regulates Fasting Glucose.

Cell Rep 2018 07;24(2):312-319

University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT, USA; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA. Electronic address:

The common genetic variation at rs8004664 in the FOXN3 gene is independently and significantly associated with fasting blood glucose, but not insulin, in non-diabetic humans. Recently, we reported that primary hepatocytes from rs8004664 hyperglycemia risk allele carriers have increased FOXN3 transcript and protein levels and liver-limited overexpression of human FOXN3, a transcriptional repressor that had not been implicated in metabolic regulation previously, increases fasting blood glucose in zebrafish. Here, we find that injection of glucagon into mice and adult zebrafish decreases liver Foxn3 protein and transcript levels. Zebrafish foxn3 loss-of-function mutants have decreased fasting blood glucose, blood glucagon, liver gluconeogenic gene expression, and α cell mass. Conversely, liver-limited overexpression of foxn3 increases α cell mass. Supporting these genetic findings in model organisms, non-diabetic rs8004664 risk allele carriers have decreased suppression of glucagon during oral glucose tolerance testing. By reciprocally regulating each other, liver FOXN3 and glucagon control fasting glucose.
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http://dx.doi.org/10.1016/j.celrep.2018.06.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086569PMC
July 2018

The ceramide ratio: a predictor of cardiometabolic risk.

J Lipid Res 2018 09 9;59(9):1549-1550. Epub 2018 Jul 9.

Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT 84112

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http://dx.doi.org/10.1194/jlr.C088377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121923PMC
September 2018

Publisher Correction: Targeting hepatic glutaminase activity to ameliorate hyperglycemia.

Nat Med 2018 Sep;24(9):1482

Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

In the version of this article initially published, the "[13C2]α-ketoglutarate" label on Fig. 1g is incorrect. It should be "[13C5]α-ketoglutarate". Additionally, in Fig. 3b, the "AAV-GFP" group is missing a notation for significance, and in Fig. 3c, the "AAV-GLS2-sh" group is missing a notation for significance. There should be a double asterisk notating significance in both panels. Finally, in the Fig. 4g legend, "[13C6]UDP-glucose" should be "[13C3]UDP-glucose", and in the Fig. 4h legend, "[13C6]hexose" should be "[13C3]hexose". The errors have been corrected in the HTML and PDF versions of this article.
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http://dx.doi.org/10.1038/s41591-018-0047-1DOI Listing
September 2018

Does This Schlank Make Me Look Fat?

Trends Endocrinol Metab 2018 09 21;29(9):597-599. Epub 2018 Apr 21.

Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112, USA. Electronic address:

Chaurasia and colleagues discuss the provocative new finding that some enzymes in the de novo sphingolipid synthesis pathway have dual roles as transcriptional regulators.
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http://dx.doi.org/10.1016/j.tem.2018.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098725PMC
September 2018

Targeting hepatic glutaminase activity to ameliorate hyperglycemia.

Nat Med 2018 05 26;24(4):518-524. Epub 2018 Mar 26.

Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Glucagon levels increase under homeostatic, fasting conditions, promoting the release of glucose from the liver by accelerating the breakdown of glycogen (also known as glycogenolysis). Glucagon also enhances gluconeogenic flux, including from an increase in the hepatic consumption of amino acids. In type 2 diabetes, dysregulated glucagon signaling contributes to the elevated hepatic glucose output and fasting hyperglycemia that occur in this condition. Yet, the mechanism by which glucagon stimulates gluconeogenesis remains incompletely understood. Contrary to the prevailing belief that glucagon acts primarily on cytoplasmic and nuclear targets, we find glucagon-dependent stimulation of mitochondrial anaplerotic flux from glutamine that increases the contribution of this amino acid to the carbons of glucose generated during gluconeogenesis. This enhanced glucose production is dependent on protein kinase A (PKA) and is associated with glucagon-stimulated calcium release from the endoplasmic reticulum, activation of mitochondrial α-ketoglutarate dehydrogenase, and increased glutaminolysis. Mice with reduced levels of hepatic glutaminase 2 (GLS2), the enzyme that catalyzes the first step in glutamine metabolism, show lower glucagon-stimulated glutamine-to-glucose flux in vivo, and GLS2 knockout results in higher fasting plasma glucagon and glutamine levels with lower fasting blood glucose levels in insulin-resistant conditions. As found in genome-wide association studies (GWAS), human genetic variation in the region of GLS2 is associated with higher fasting plasma glucose; here we show in human cryopreserved primary hepatocytes in vitro that these natural gain-of-function missense mutations in GLS2 result in higher glutaminolysis and glucose production. These data emphasize the importance of gluconeogenesis from glutamine, particularly in pathological states of increased glucagon signaling, while suggesting a possible new therapeutic avenue to treat hyperglycemia.
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http://dx.doi.org/10.1038/nm.4514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089616PMC
May 2018

POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels.

Elife 2018 03 12;7. Epub 2018 Mar 12.

Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States.

Leptin is critical for energy balance, glucose homeostasis, and for metabolic and neuroendocrine adaptations to starvation. A prevalent model predicts that leptin's actions are mediated through pro-opiomelanocortin (POMC) neurons that express leptin receptors (LEPRs). However, previous studies have used prenatal genetic manipulations, which may be subject to developmental compensation. Here, we tested the direct contribution of POMC neurons expressing LEPRs in regulating energy balance, glucose homeostasis and leptin secretion during fasting using a spatiotemporally controlled expression mouse model. We report a dissociation between leptin's effects on glucose homeostasis versus energy balance in POMC neurons. We show that these neurons are dispensable for regulating food intake, but are required for coordinating hepatic glucose production and for the fasting-induced fall in leptin levels, independent of changes in fat mass. We also identify a role for sympathetic nervous system regulation of the inhibitory adrenergic receptor (ADRA2A) in regulating leptin production. Collectively, our findings highlight a previously unrecognized role of POMC neurons in regulating leptin levels.
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http://dx.doi.org/10.7554/eLife.33710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866097PMC
March 2018

De novo adipocyte differentiation from Pdgfrβ preadipocytes protects against pathologic visceral adipose expansion in obesity.

Nat Commun 2018 03 1;9(1):890. Epub 2018 Mar 1.

Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

Pathologic expansion of white adipose tissue (WAT) in obesity is characterized by adipocyte hypertrophy, inflammation, and fibrosis; however, factors triggering this maladaptive remodeling are largely unknown. Here, we test the hypothesis that the potential to recruit new adipocytes from Pdgfrβ preadipocytes determines visceral WAT health in obesity. We manipulate levels of Pparg, the master regulator of adipogenesis, in Pdgfrβ precursors of adult mice. Increasing the adipogenic capacity of Pdgfrβ precursors through Pparg overexpression results in healthy visceral WAT expansion in obesity and adiponectin-dependent improvements in glucose homeostasis. Loss of mural cell Pparg triggers pathologic visceral WAT expansion upon high-fat diet feeding. Moreover, the ability of the TZD class of anti-diabetic drugs to promote healthy visceral WAT remodeling is dependent on mural cell Pparg. These data highlight the protective effects of de novo visceral adipocyte differentiation in these settings, and suggest Pdgfrβ adipocyte precursors as targets for therapeutic intervention in diabetes.
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http://dx.doi.org/10.1038/s41467-018-03196-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832777PMC
March 2018

Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity.

J Clin Invest 2018 03 19;128(3):1178-1189. Epub 2018 Feb 19.

Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern (UTSW) Medical Center, Dallas, Texas, USA.

The compensatory proliferation of insulin-producing β cells is critical to maintaining glucose homeostasis at the early stage of type 2 diabetes. Failure of β cells to proliferate results in hyperglycemia and insulin dependence in patients. To understand the effect of the interplay between β cell compensation and lipid metabolism upon obesity and peripheral insulin resistance, we eliminated LDL receptor-related protein 1 (LRP1), a pleiotropic mediator of cholesterol, insulin, energy metabolism, and other cellular processes, in β cells. Upon high-fat diet exposure, LRP1 ablation significantly impaired insulin secretion and proliferation of β cells. The diminished insulin signaling was partly contributed to by the hypersensitivity to glucose-induced, Ca2+-dependent activation of Erk and the mTORC1 effector p85 S6K1. Surprisingly, in LRP1-deficient islets, lipotoxic sphingolipids were mitigated by improved lipid metabolism, mediated at least in part by the master transcriptional regulator PPARγ2. Acute overexpression of PPARγ2 in β cells impaired insulin signaling and insulin secretion. Elimination of Apbb2, a functional regulator of LRP1 cytoplasmic domain, also impaired β cell function in a similar fashion. In summary, our results uncover the double-edged effects of intracellular lipid metabolism on β cell function and viability in obesity and type 2 diabetes and highlight LRP1 as an essential regulator of these processes.
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http://dx.doi.org/10.1172/JCI97702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824868PMC
March 2018