Publications by authors named "Irwin J Kurland"

46 Publications

Deciphering structural bases of intestinal and hepatic selectivity in targeting pregnane X receptor with indole-based microbial mimics.

Bioorg Chem 2021 Jan 22;109:104661. Epub 2021 Jan 22.

Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic. Electronic address:

Microbial metabolite mimicry is a new concept that promises to deliver compounds that have minimal liabilities and enhanced therapeutic effects in a host. In a previous publication, we have shown that microbial metabolites of L-tryptophan, indoles, when chemically altered, yielded potent anti-inflammatory pregnane X Receptor (PXR)-targeting lead compounds, FKK5 and FKK6, targeting intestinal inflammation. Our aim in this study was to further define structure-activity relationships between indole analogs and PXR, we removed the phenyl-sulfonyl group or replaced the pyridyl residue with imidazolopyridyl of FKK6. Our results showed that while removal of the phenyl-sulfonyl group from FKK6 (now called CVK003) shifts agonist activity away from PXR towards the aryl hydrocarbon receptor (AhR), the imidazolopyridyl addition preserves PXR activity in vitro. However, when these compounds are administered to mice, that unlike the parent molecule, FKK6, they exhibit poor induction of PXR target genes in the intestines and the liver. These data suggest that modifications of FKK6 specifically in the pyridyl moiety can result in compounds with weak PXR activity in vivo. These observations are a significant step forward for understanding the structure-activity relationships (SAR) between indole mimics and receptors, PXR and AhR.
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http://dx.doi.org/10.1016/j.bioorg.2021.104661DOI Listing
January 2021

Plasma metabolomic profiles in liver cancer patients following stereotactic body radiotherapy.

EBioMedicine 2020 Sep 3;59:102973. Epub 2020 Sep 3.

Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada. Electronic address:

Background: Stereotactic body radiotherapy (SBRT) is an effective treatment for hepatocellular carcinoma (HCC). This study sought to identify differentially expressed plasma metabolites in HCC patients at baseline and early during SBRT, and to explore if changes in these metabolites early during SBRT may serve as biomarkers for radiation-induced liver injury and/or tumour response.

Methods: Forty-seven HCC patients were treated with SBRT on previously published prospective trials. Plasma samples were collected at baseline and after one to two fractions of SBRT, and analysed by GC/MS and LC/MS for untargeted and targeted metabolomics profiling, respectively.

Findings: Sixty-nine metabolites at baseline and 62 metabolites after one to two fractions of SBRT were differentially expressed, and strongly separated the Child Pugh (CP) B from the CP A HCC patients. These metabolites are associated with oxidative stress and alterations in hepatic cellular metabolism. Differential upregulation of serine, alanine, taurine, and lipid metabolites early during SBRT from baseline was noted in the HCC patients who demonstrated the greatest increase in CP scores at three months post SBRT, suggesting that high protein and lipid turnover early during SBRT may portend increased clinical liver toxicity. Twenty annotated metabolites including fatty acids, glycerophospholipids, and acylcarnitines were differentially upregulated early during SBRT from baseline and separated patients with complete/partial response from those with stable disease at three months post SBRT.

Interpretation: Dysregulation of amino acid and lipid metabolism detected early during SBRT are associated with subsequent clinical liver injury and tumour response in HCC.
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http://dx.doi.org/10.1016/j.ebiom.2020.102973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484529PMC
September 2020

Altered Gut Microbiota and Host Metabolite Profiles in Women With Human Immunodeficiency Virus.

Clin Infect Dis 2020 Dec;71(9):2345-2353

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA.

Background: Alterations in gut microbiota (GMB) and host metabolites have been noted in individuals with HIV. However, it remains unclear whether alterations in GMB and related functional groups contribute to disrupted host metabolite profiles in these individuals.

Methods: This study included 185 women (128 with longstanding HIV infection, 88% under antiretroviral therapy; and 57 women without HIV from the same geographic location with comparable characteristics). Stool samples were analyzed by 16S rRNA V4 region sequencing, and GMB function was inferred by PICRUSt. Plasma metabolomic profiling was performed using liquid chromatography-tandem mass spectrometry, and 133 metabolites (amino acids, biogenic amines, acylcarnitines, and lipids) were analyzed.

Results: Four predominant bacterial genera were identified as associated with HIV infection, with higher abundances of Ruminococcus and Oscillospira and lower abundances of Bifidobacterium and Collinsella in women with HIV than in those without. Women with HIV showed a distinct plasma metabolite profile, which featured elevated glycerophospholipid levels compared with those without HIV. Functional analyses also indicated that GMB lipid metabolism was enriched in women with HIV. Ruminococcus and Oscillospira were among the top bacterial genera contributing to the GMB glycerophospholipid metabolism pathway and showed positive correlations with host plasma glycerophospholipid levels. One bacterial functional capacity in the acetate and propionate biosynthesis pathway was identified to be mainly contributed by Bifidobacterium; this functional capacity was lower in women with HIV than in women without HIV.

Conclusions: Our integrative analyses identified altered GMB with related functional capacities that might be associated with disrupted plasma metabolite profiles in women with HIV.
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http://dx.doi.org/10.1093/cid/ciz1117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713676PMC
December 2020

Lactate Efflux From Intervertebral Disc Cells Is Required for Maintenance of Spine Health.

J Bone Miner Res 2020 03 12;35(3):550-570. Epub 2019 Dec 12.

Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA, USA.

Maintenance of glycolytic metabolism is postulated to be required for health of the spinal column. In the hypoxic tissues of the intervertebral disc and glycolytic cells of vertebral bone, glucose is metabolized into pyruvate for ATP generation and reduced to lactate to sustain redox balance. The rise in intracellular H /lactate concentrations are balanced by plasma-membrane monocarboxylate transporters (MCTs). Using MCT4 null mice and human tissue samples, complemented with genetic and metabolic approaches, we determine that H /lactate efflux is critical for maintenance of disc and vertebral bone health. Mechanistically, MCT4 maintains glycolytic and tricarboxylic acid (TCA) cycle flux and intracellular pH homeostasis in the nucleus pulposus compartment of the disc, where hypoxia-inducible factor 1α (HIF-1α) directly activates an intronic enhancer in SLC16A3. Ultimately, our results provide support for research into lactate as a diagnostic biomarker for chronic, painful, disc degeneration. © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064427PMC
March 2020

Phenotypic Modulation of Skeletal Muscle Fibers in LPIN1-Deficient Lipodystrophic ( fld) Mice.

Vet Pathol 2019 03 31;56(2):322-331. Epub 2018 Oct 31.

3 Department of Medicine (Endocrinology), Albert Einstein College of Medicine, Bronx, NY, USA.

Lipin-1 ( Lpin1)-deficient lipodystrophic mice have scant and immature adipocytes and develop transient fatty liver early in life. Unlike normal mice, these mice cannot rely on stored triglycerides to generate adenosine triphosphate (ATP) from the β-oxidation of fatty acids during periods of fasting. To compensate, these mice store much higher amounts of glycogen in skeletal muscle and liver than wild-type mice in order to support energy needs during periods of fasting. Our studies demonstrated that there are phenotypic changes in skeletal muscle fibers that reflect an adaptation to this unique metabolic situation. The phenotype of skeletal muscle (soleus, gastrocnemius, plantaris, and extensor digitorum longus [EDL]) from Lpin1 was evaluated using various methods including immunohistochemistry for myosin heavy chains (Myh) 1, 2, 2a, 2b, and 2x; enzyme histochemistry for myosin ATPase, cytochrome-c oxidase (COX), and succinyl dehydrogenase (SDH); periodic acid-Schiff; and transmission electron microscopy. Fiber-type changes in the soleus muscle of Lpin1 mice were prominent and included decreased Myh1 expression with concomitant increases in Myh2 expression and myosin-ATPase activity; this change was associated with an increase in the presence of Myh1/2a or Myh1/2x hybrid fibers. Alterations in mitochondrial enzyme activity (COX and SDH) were apparent in the myofibers in the soleus, gastrocnemius, plantaris, and EDL muscles. Electron microscopy revealed increases in the subsarcolemmal mitochondrial mass in the muscles of Lpin1 mice. These data demonstrate that lipin-1 deficiency results in phenotypic fiber-specific modulation of skeletal muscle necessary for compensatory fuel utilization adaptations in lipodystrophy.
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http://dx.doi.org/10.1177/0300985818809126DOI Listing
March 2019

Gut microbiota and plasma metabolites associated with diabetes in women with, or at high risk for, HIV infection.

EBioMedicine 2018 Nov 23;37:392-400. Epub 2018 Oct 23.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address:

Background: Gut microbiota alteration has been implicated in HIV infection and metabolic disorders. The relationship between gut microbiota and diabetes has rarely been studied in HIV-infected individuals, who have excess risk of metabolic disorders.

Methods: Our study during 2015-2016 enrolled predominantly African Americans and Hispanics in the Women's Interagency HIV Study. We studied 28 women with long-standing HIV infection under antiretroviral therapy and 20 HIV-uninfected, but at high risk of infection, women (16 HIV+ and 6 HIV- with diabetes). Fecal samples were analyzed by sequencing prokaryotic16S rRNA gene. Plasma metabolomics profiling was performed by liquid chromatography-tandem mass spectrometry.

Findings: No significant differences in bacterial α- or β-diversity were observed by diabetes or HIV serostatus (all P > .1). Relative abundances of four genera (Finegoldia, Anaerococcus, Sneathia, and Adlercreutzia) were lower in women with diabetes compared to those without diabetes (all P < .01). In women with diabetes, plasma levels of several metabolites in tryptophan catabolism (e,g., kynurenine/tryptophan ratio), branched-chain amino acid and proline metabolism pathways were higher, while glycerophospholipids were lower (all P < .05). Results were generally consistent between HIV-infected and HIV-uninfected women, and no significant modification effects by HIV serostatus were observed (all P > 0.05). Anaerococcus, known to produce butyrate which is involved in anti-inflammation and glucose metabolism, showed an inverse correlation with kynurenine/tryptophan ratio (r = -0.38, P < .01).

Interpretation: Among women with or at high risk for HIV infection, diabetes is associated with gut microbiota and plasma metabolite alteration, including depletion of butyrate-producing bacterial population along with higher tryptophan catabolism. FUND: NHLBI (K01HL129892, R01HL140976) and FMF.
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http://dx.doi.org/10.1016/j.ebiom.2018.10.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286648PMC
November 2018

Sarcosine Is Uniquely Modulated by Aging and Dietary Restriction in Rodents and Humans.

Cell Rep 2018 10;25(3):663-676.e6

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address:

A hallmark of aging is a decline in metabolic homeostasis, which is attenuated by dietary restriction (DR). However, the interaction of aging and DR with the metabolome is not well understood. We report that DR is a stronger modulator of the rat metabolome than age in plasma and tissues. A comparative metabolomic screen in rodents and humans identified circulating sarcosine as being similarly reduced with aging and increased by DR, while sarcosine is also elevated in long-lived Ames dwarf mice. Pathway analysis in aged sarcosine-replete rats identify this biogenic amine as an integral node in the metabolome network. Finally, we show that sarcosine can activate autophagy in cultured cells and enhances autophagic flux in vivo, suggesting a potential role in autophagy induction by DR. Thus, these data identify circulating sarcosine as a biomarker of aging and DR in mammalians and may contribute to age-related alterations in the metabolome and in proteostasis.
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http://dx.doi.org/10.1016/j.celrep.2018.09.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280974PMC
October 2018

Comparison of Fecal Collection Methods for Microbiome and Metabolomics Studies.

Front Cell Infect Microbiol 2018 28;8:301. Epub 2018 Aug 28.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, United States.

Integrated microbiome and metabolomics analyses hold the potential to reveal interactions between host and microbiota in relation to disease risks. However, there are few studies evaluating how field methods influence fecal microbiome characterization and metabolomics profiling. Five fecal collection methods [immediate freezing at -20°C without preservative, OMNIgene GUT, 95% ethanol, RNA, and Flinders Technology Associates (FTA) cards] were used to collect 40 fecal samples from eight healthy volunteers. We performed gut microbiota 16S rRNA sequencing, untargeted metabolomics profiling, and targeted metabolomics focusing on short chained fatty acids (SCFAs). Metrics included α-diversity and β-diversity as well as distributions of predominant phyla. To evaluate the concordance with the "gold standard" immediate freezing, the intraclass correlation coefficients (ICCs) for alternate fecal collection systems were calculated. Correlations between SCFAs and gut microbiota were also examined. The FTA cards had the highest ICCs compared to the immediate freezing method for α-diversity indices (ICCs = 0.96, 0.96, 0.76 for Shannon index, Simpson's Index, Chao-1 Index, respectively), followed by OMNIgene GUT, RNA, and 95% ethanol. High ICCs (all >0.88) were observed for all methods for the β-diversity metric. For untargeted metabolomics, in comparison to immediate freezing which detected 621 metabolites at ≥75% detectability level, 95% ethanol showed the largest overlapping set of metabolites ( = 430; 69.2%), followed by FTA cards ( = 330; 53.1%) and OMNIgene GUT ( = 213; 34.3%). Both OMNIgene GUT (ICCs = 0.82, 0.93, 0.64) and FTA cards (ICCs = 0.87, 0.85, 0.54) had acceptable ICCs for the top three predominant SCFAs (butyric acid, propionic acid and acetic acid). Nominally significant correlations between bacterial genera and SCFAs ( < 0.05) were observed in fecal samples collected by different methods. Of note, a high correlation between the genus (known butyrate producer) and butyric acid was observed for both immediate freezing ( = 0.83) and FTA cards ( = 0.74). Four alternative fecal collection methods are generally comparable with immediate freezing, but there are differences in certain measures of the gut microbiome and fecal metabolome across methods. Choice of method depends on the research interests, simplicity of fecal collection procedures and ease of transportation to the lab, especially for large epidemiological studies.
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http://dx.doi.org/10.3389/fcimb.2018.00301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127643PMC
August 2019

Effect of Maternal Smoking on Plasma and Urinary Measures of Vitamin E Isoforms in the First Month after Extreme Preterm Birth.

J Pediatr 2018 06 2;197:280-285.e3. Epub 2018 Feb 2.

Division of Neonatology, Department of Pediatrics, Albert Einstein College of Medicine and the Children's Hospital at Montefiore, Bronx, NY.

We examined the effect of maternal smoking on plasma and urinary levels of vitamin E isoforms in preterm infants. Maternal smoking during pregnancy decreased infant plasma alpha- and gamma-tocopherol concentrations at 1 week and 4 weeks, with 45% of infants of smokers deficient in alpha-tocopherol at 1 month after birth.
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http://dx.doi.org/10.1016/j.jpeds.2017.12.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971015PMC
June 2018

Enhanced Isotopic Ratio Outlier Analysis (IROA) Peak Detection and Identification with Ultra-High Resolution GC-Orbitrap/MS: Potential Application for Investigation of Model Organism Metabolomes.

Metabolites 2018 Jan 18;8(1). Epub 2018 Jan 18.

Stable Isotope and Metabolomics Core Facility, Diabetes Center, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Identifying non-annotated peaks may have a significant impact on the understanding of biological systems. In silico methodologies have focused on ESI LC/MS/MS for identifying non-annotated MS peaks. In this study, we employed in silico methodology to develop an Isotopic Ratio Outlier Analysis (IROA) workflow using enhanced mass spectrometric data acquired with the ultra-high resolution GC-Orbitrap/MS to determine the identity of non-annotated metabolites. The higher resolution of the GC-Orbitrap/MS, together with its wide dynamic range, resulted in more IROA peak pairs detected, and increased reliability of chemical formulae generation (CFG). IROA uses two different C-enriched carbon sources (randomized 95% C and 95% C) to produce mirror image isotopologue pairs, whose mass difference reveals the carbon chain length (n), which aids in the identification of endogenous metabolites. Accurate m/z, n, and derivatization information are obtained from our GC/MS workflow for unknown metabolite identification, and aids in silico methodologies for identifying isomeric and non-annotated metabolites. We were able to mine more mass spectral information using the same growth protocol (Qiu et al. Anal. Chem 2016) with the ultra-high resolution GC-Orbitrap/MS, using 10% ammonia in methane as the CI reagent gas. We identified 244 IROA peaks pairs, which significantly increased IROA detection capability compared with our previous report (126 IROA peak pairs using a GC-TOF/MS machine). For 55 selected metabolites identified from matched IROA CI and EI spectra, using the GC-Orbitrap/MS vs. GC-TOF/MS, the average mass deviation for GC-Orbitrap/MS was 1.48 ppm, however, the average mass deviation was 32.2 ppm for the GC-TOF/MS machine. In summary, the higher resolution and wider dynamic range of the GC-Orbitrap/MS enabled more accurate CFG, and the coupling of accurate mass GC/MS IROA methodology with in silico fragmentation has great potential in unknown metabolite identification, with applications for characterizing model organism networks.
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http://dx.doi.org/10.3390/metabo8010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875999PMC
January 2018

Mangiferin Accelerates Glycolysis and Enhances Mitochondrial Bioenergetics.

Int J Mol Sci 2018 Jan 9;19(1). Epub 2018 Jan 9.

Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

One of the main causes of hyperglycemia is inefficient or impaired glucose utilization by skeletal muscle, which can be exacerbated by chronic high caloric intake. Previously, we identified a natural compound, mangiferin (MGF) that improved glucose utilization in high fat diet (HFD)-induced insulin resistant mice. To further identify the molecular mechanisms of MGF action on glucose metabolism, we conducted targeted metabolomics and transcriptomics studies of glycolyic and mitochondrial bioenergetics pathways in skeletal muscle. These data revealed that MGF increased glycolytic metabolites that were further augmented as glycolysis proceeded from the early to the late steps. Consistent with an MGF-stimulation of glycolytic flux there was a concomitant increase in the expression of enzymes catalyzing glycolysis. MGF also increased important metabolites in the tricarboxylic acid (TCA) cycle, such as α-ketoglutarate and fumarate. Interestingly however, there was a reduction in succinate, a metabolite that also feeds into the electron transport chain to produce energy. MGF increased succinate clearance by enhancing the expression and activity of succinate dehydrogenase, leading to increased ATP production. At the transcriptional level, MGF induced mRNAs of mitochondrial genes and their transcriptional factors. Together, these data suggest that MGF upregulates mitochondrial oxidative capacity that likely drives the acceleration of glycolysis flux.
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http://dx.doi.org/10.3390/ijms19010201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796150PMC
January 2018

Optimization of GC/TOF MS analysis conditions for assessing host-gut microbiota metabolic interactions: Chinese rhubarb alters fecal aromatic amino acids and phenol metabolism.

Anal Chim Acta 2017 Dec 19;995:21-33. Epub 2017 Oct 19.

Center for Instrumental Analysis, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address:

In this paper, an optimized method based on gas chromatography/time-of-flight mass spectrometry (GC-TOFMS) platform has been developed for the analysis of gut microbial-host related co-metabolites in fecal samples. The optimization was performed with proportion of chloroform (C), methanol (M) and water (W) for the extraction of specific metabolic pathways of interest. Loading Bi-plots from the PLS regression model revealed that high concentration of chloroform emphasized the extraction of short chain fatty acids and TCA intermediates, while the higher concentration of methanol emphasized indole and phenyl derivatives. Low level of organic solution emphasized some TCA intermediates but not for indole and phenyl species. The highest sum of the peak area and the distribution of metabolites corresponded to the extraction of methanol/chloroform/water of 225:75:300 (v/v/v), which was then selected for method validation and utilized in our application. Excellent linearity was obtained with 62 reference standards representing different classes of gut microbial-host related co-metabolites, with correlation coefficients (r) higher than 0.99. Limit of detections (LODs) and limit of qualifications (LOQs) for these standards were below 0.9 nmol and 1.6 nmol, respectively. The reproducibility and repeatability of the majority of tested metabolites in fecal samples were observed with RSDs lower than 15%. Chinese rhubarb-treated rats had elevated indole and phenyl species, and decreased levels of polyamine such as putrescine, and several amino acids. Our optimized method has revealed host-microbe relationships of potential importance for intestinal microbial metabolite receptors such as pregnane X receptor (PXR) and aryl hydrocarbon receptor (AHR) activity, and for enzymes such as ornithine decarboxylase (ODC).
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http://dx.doi.org/10.1016/j.aca.2017.09.042DOI Listing
December 2017

Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma.

J Lipid Res 2017 12 6;58(12):2275-2288. Epub 2017 Oct 6.

Lipidomics Core Facility and Department of Pathology, Wayne State University, Detroit, MI.

As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950-Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each laboratory using a different lipidomics workflow. A total of 1,527 unique lipids were measured across all laboratories and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra- and interlaboratory quality control and method validation. These analyses were performed using nonstandardized laboratory-independent workflows. The consensus locations were also compared with a previous examination of SRM 1950 by the LIPID MAPS consortium. While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.
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http://dx.doi.org/10.1194/jlr.M079012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711491PMC
December 2017

Lower mitochondrial DNA and altered mitochondrial fuel metabolism in HIV-exposed uninfected infants in Cameroon.

AIDS 2017 11;31(18):2475-2481

aDepartment of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York bDepartment of Pediatrics and Internal Medicine, Massachusetts General Hospital cDepartment of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts dDepartment of Medical Genetics, University of Mississippi Medical Center, Jackson, Mississippi, USA eCameroon Baptist Convention Health Services, Bamenda, Cameroon fICAP, Mailman School of Public Health and College of Physicians and Surgeons, Columbia University gDepartment of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York hKeck School of Medicine of USC, The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California iDepartment of Medicine, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine, Bronx, New York, USA jDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Objective: Evaluate blood mitochondrial DNA (mtDNA) content in HIV/antiretroviral-exposed uninfected (HEU) vs. HIV-unexposed uninfected (HUU) infants and investigate differences in mitochondrial-related metabolites by exposure group.

Design: We enrolled a prospective cohort of HIV-infected and HIV-uninfected pregnant woman/infant pairs in Cameroon.

Methods: Dried blood spot mtDNA : nuclear DNA ratio was measured by monochrome multiplex quantitative polymerase chain reaction in HEU infants exposed to in-utero antiretrovirals and postnatal zidovudine (HEU-Z) or nevirapine (HEU-N), and in HUU infants at 6 weeks of life. Acylcarnitines and branch-chain amino acids (BCAAs) were measured via tandem mass spectrometry and consolidated into seven uncorrelated components using principal component analysis. Linear regression models were fit to assess the association between in-utero/postnatal HIV/antiretroviral exposure and infant mtDNA, adjusting for confounders and principal component analysis-derived acylcarnitine/BCAA component scores.

Results: Of 364 singleton infants, 38 were HEU-Z, 117 HEU-N, and 209 HUU. Mean mtDNA content was lowest in HEU-Z infants (140 vs. 160 in HEU-N vs. 174 in HUU, P = 0.004). After adjusting for confounders, HEU-Z infants remained at increased risk for lower mtDNA content compared with HUU infants (β: -4.46, P = 0.045), whereas HEU-N infants did not, compared with HUU infants (β: -1.68, P = 0.269. Furthermore, long-chain acylcarnitines were associated with lower (β: -2.35, P = 0.002) and short-chain and BCAA-related acylcarnitines were associated with higher (β: 2.96, P = 0.001) mtDNA content.

Conclusion: Compared with HUU infants, HEU infants receiving postnatal zidovudine appear to be at increased risk for decreased blood mtDNA content which may be associated with altered mitochondrial fuel utilization in HEU-Z infants.
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http://dx.doi.org/10.1097/QAD.0000000000001647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680102PMC
November 2017

How close are we to complete annotation of metabolomes?

Curr Opin Chem Biol 2017 02 21;36:64-69. Epub 2017 Jan 21.

School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Phenome Centre Birmingham, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

The metabolome describes the full complement of the tens to hundreds of thousands of low molecular weight metabolites present within a biological system. Identification of the metabolome is critical for discovering the maximum amount of biochemical knowledge from metabolomics datasets. Yet no exhaustive experimental characterisation of any organismal metabolome has been reported to date, dramatically contrasting with the genome sequencing of thousands of plants, animals and microbes. Here, we review the status of metabolome annotation and describe advances in the analytical methodologies being applied. In part through new international coordination, we conclude that we are now entering a new era of metabolome annotation.
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http://dx.doi.org/10.1016/j.cbpa.2017.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337156PMC
February 2017

Obesity paradox, obesity orthodox, and the metabolic syndrome: An approach to unity.

Mol Med 2017 Feb 16;22:873-885. Epub 2016 Nov 16.

Laboratory of Diabetes and Diabetes-Related Research, Feinstein Institute for Medical Research, 8 Northwell Health, Manhasset, NY.

Obesity and the accompanying metabolic syndrome are strongly associated with heightened morbidity and mortality in older adults. In our review of more than 20 epidemiologic studies of major infectious diseases, including leaders such as tuberculosis, community-acquired pneumonia, and sepsis, obesity was associated with better outcomes. A cause-and-effect relationship between over-nutrition and survival with infection is suggested by results of two preliminary studies of infections in mice, where high fat feeding for 8-10 weeks provided much better outcomes. The better outcomes of infections with obesity are reminiscent of many recent studies of "sterile" non-infectious medical and surgical conditions where outcomes for obese patients are better than for their thinner counterparts --- and given the tag "obesity paradox". Turning to the history of medicine and biological evolution, we hypothesize that the metabolic syndrome has very ancient origins and is part of a lifelong metabolic program. While part of that program (the metabolic syndrome) promotes morbidity and mortality with aging, it helps infants and children as well as adults in their fight against infections and recovery from injuries, key roles in the hundreds of centuries before the public health advances of the 20th century. We conclude with speculation on how understanding the biological elements that protect obese patients with infections or injuries might be applied advantageously to thin patients with the same medical challenges.
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http://dx.doi.org/10.2119/molmed.2016.00211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319205PMC
February 2017

Diets High in Fat or Fructose Differentially Modulate Bone Health and Lipid Metabolism.

Calcif Tissue Int 2017 01 10;100(1):20-28. Epub 2016 Nov 10.

Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, 11794-5281, USA.

Diets high in fat or carbohydrates can lead to obesity and diabetes, two interrelated conditions that have been associated with osteoporosis. Here, we contrasted the effects of a high fat (HF) versus fructose-enriched carbohydrate (CH) versus regular chow (SC) diet on bone morphology, fat content and metabolic balance in BALB/cByJ mice over a 15-week period. For 13 weeks, there were no differences in body mass between groups with small differences in the last 2 weeks. Even without the potentially confounding factor of altered body mass and levels of load bearing, HF consumption was detrimental to bone in the distal femur with lower trabecular bone volume fraction and thinner cortices than controls. These differences in bone were accompanied by twofold greater abdominal fat content and fourfold greater plasma leptin concentrations. High-fat feeding caused a decrease in de-novo lipid synthesis in the liver, kidney, white adipose and brown adipose tissue. In contrast to HF, the fructose diet did not significantly impact bone quantity or architecture. Fructose consumption also did not significantly alter leptin levels or de-novo lipid synthesis but reduced epididymal adipose tissue and increased brown adipose tissue. Cortical stiffness was lower in the CH than in HF mice. There were no differences in glucose or insulin levels between groups. Together, a diet high in fat had a negative influence on bone structure, adipose tissue deposition and lipid synthesis, changes that were largely avoided with a fructose-enriched diet.
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http://dx.doi.org/10.1007/s00223-016-0205-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217484PMC
January 2017

The Time Is Right to Focus on Model Organism Metabolomes.

Metabolites 2016 Feb 15;6(1). Epub 2016 Feb 15.

School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK.

Model organisms are an essential component of biological and biomedical research that can be used to study specific biological processes. These organisms are in part selected for facile experimental study. However, just as importantly, intensive study of a small number of model organisms yields important synergies as discoveries in one area of science for a given organism shed light on biological processes in other areas, even for other organisms. Furthermore, the extensive knowledge bases compiled for each model organism enable systems-level understandings of these species, which enhance the overall biological and biomedical knowledge for all organisms, including humans. Building upon extensive genomics research, we argue that the time is now right to focus intensively on model organism metabolomes. We propose a grand challenge for metabolomics studies of model organisms: to identify and map all metabolites onto metabolic pathways, to develop quantitative metabolic models for model organisms, and to relate organism metabolic pathways within the context of evolutionary metabolomics, i.e., phylometabolomics. These efforts should focus on a series of established model organisms in microbial, animal and plant research.
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http://dx.doi.org/10.3390/metabo6010008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812337PMC
February 2016

Isotopic Ratio Outlier Analysis of the S. cerevisiae Metabolome Using Accurate Mass Gas Chromatography/Time-of-Flight Mass Spectrometry: A New Method for Discovery.

Anal Chem 2016 Mar 17;88(5):2747-54. Epub 2016 Feb 17.

Stable Isotope and Metabolomics Core Facility, Diabetes Center, Department of Medicine, Albert Einstein College of Medicine , Bronx, New York 10461, United States.

Isotopic ratio outlier analysis (IROA) is a (13)C metabolomics profiling method that eliminates sample to sample variance, discriminates against noise and artifacts, and improves identification of compounds, previously done with accurate mass liquid chromatography/mass spectrometry (LC/MS). This is the first report using IROA technology in combination with accurate mass gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS), here used to examine the S. cerevisiae metabolome. S. cerevisiae was grown in YNB media, containing randomized 95% (13)C, or 5%(13)C glucose as the single carbon source, in order that the isotopomer pattern of all metabolites would mirror the labeled glucose. When these IROA experiments are combined, the abundance of the heavy isotopologues in the 5%(13)C extracts, or light isotopologues in the 95%(13)C extracts, follows the binomial distribution, showing mirrored peak pairs for the molecular ion. The mass difference between the (12)C monoisotopic and the (13)C monoisotopic equals the number of carbons in the molecules. The IROA-GC/MS protocol developed, using both chemical and electron ionization, extends the information acquired from the isotopic peak patterns for formulas generation. The process that can be formulated as an algorithm, in which the number of carbons, as well as the number of methoximations and silylations are used as search constraints. In electron impact (EI/IROA) spectra, the artifactual peaks are identified and easily removed, which has the potential to generate "clean" EI libraries. The combination of chemical ionization (CI) IROA and EI/IROA affords a metabolite identification procedure that enables the identification of coeluting metabolites, and allowed us to characterize 126 metabolites in the current study.
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http://dx.doi.org/10.1021/acs.analchem.5b04263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052867PMC
March 2016

Lower Preprandial Insulin and Altered Fuel Use in HIV/Antiretroviral-Exposed Infants in Cameroon.

J Clin Endocrinol Metab 2015 Sep 2;100(9):3260-9. Epub 2015 Jul 2.

Departments of Medicine (J.J.), Obstetrics, Gynecology, and Reproductive Science (J.J.), Genetics and Genomic Sciences (C.Y.), and Obstetrics, Gynecology, and Reproductive Science (R.S.S.), and Department of Medicine (D.L.), Division of Endocrinology, Icahn School of Medicine, Mt Sinai, New York, New York 10029; Department of Pediatrics (B.K.), Division of Genetics and Metabolism, Children's National Medical Center/George Washington University School of Medicine, Washington, DC 20037; Department of Medicine (Y.Q., I.J.K.), Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York 10461; Departments of Pediatrics and Internal Medicine (K.P.), Massachusetts General Hospital, Boston, Massachusetts 02114; Cameroon Baptist Convention Health Services (E.N., F.E., P.M.T.), Bamenda, Cameroon; ICAP (E.J.A.), Mailman School of Public Health and College of Physicians and Surgeons, Columbia University, New York, New York 10032; and The Saban Research Institute of Children's Hospital Los Angeles (M.E.G.), Keck School of Medicine of University of Southern California, Los Angeles, California 90033.

Context: Intrauterine HIV/antiretroviral (ARV) and postnatal ARVs are known to perturb energy metabolism and could have permanent effects on future metabolic health. Such maladaptive effects could be mediated by changes in mitochondrial function and intermediary metabolism due to fetal and early-life ARV exposure in HIV/ARV-exposed uninfected (HEU) infants.

Objective: The objective of the study was to understand the relationship(s) between mitochondrial fuel use (assessed via acylcarnitines and branched chain amino acids) and preprandial insulin in infants exposed to in utero HIV/ARV plus postnatal zidovudine or nevirapine compared with HIV/ARV-unexposed uninfected (HUU) infants.

Design: This was a prospective cohort study with the following three groups: 1) intrauterine HIV/ARV/postnatal zidovudine-exposed (HEU-A), 2) intrauterine HIV/ARV/postnatal nevirapine-exposed (HEU-N), and 3) HUU infants. Principal component analysis and linear regression modeling were performed to assess the association between in utero HIV/ARV exposure and infant insulin.

Setting: The study was conducted at Cameroonian urban antenatal centers.

Participants: HIV-infected and -uninfected pregnant woman/infant dyads participated in the study.

Main Outcome: Preprandial insulin was the main outcome measured.

Results: Of 366 infants, 38 were HEU-A, 118 HEU-N. Forty intermediary metabolites were consolidated into seven principal components. In a multivariate analysis, both HEU-A (β = -.116, P= .012) and HEU-N (β = -.070, P= .022) demonstrated lower insulin compared with HUU infants. However, at high levels of plasma metabolites, HEU-A (β = .027, P= .050) exhibited higher insulin levels than HEU-N or HUU infants. A unique array of short-chain acylcarnitines (β = .044, P= .001) and branched-chain amino acids (β = .033, P= .012) was associated with insulin.

Conclusion: HEU-A and HEU-N infants have lower preprandial insulin levels at 6 weeks of age and appear to use metabolic fuel substrates differently than HUU infants. Future studies are warranted to determine whether observed differences have lasting metabolic implications, such as later insulin resistance.
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http://dx.doi.org/10.1210/JC.2015-2198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570172PMC
September 2015

Intestinal microbiota-derived metabolomic blood plasma markers for prior radiation injury.

Int J Radiat Oncol Biol Phys 2015 Feb;91(2):360-7

Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York; Department of Mathematical Sciences, Yeshiva University, New York, New York. Electronic address:

Purpose: Assessing whole-body radiation injury and absorbed dose is essential for remediation efforts following accidental or deliberate exposure in medical, industrial, military, or terrorist incidents. We hypothesize that variations in specific metabolite concentrations extracted from blood plasma would correlate with whole-body radiation injury and dose.

Methods And Materials: Groups of C57BL/6 mice (n=12 per group) were exposed to 0, 2, 4, 8, and 10.4 Gy of whole-body gamma radiation. At 24 hours after treatment, all animals were euthanized, and both plasma and liver biopsy samples were obtained, the latter being used to identify a distinct hepatic radiation injury response within plasma. A semiquantitative, untargeted metabolite/lipid profile was developed using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry, which identified 354 biochemical compounds. A second set of C57BL/6 mice (n=6 per group) were used to assess a subset of identified plasma markers beyond 24 hours.

Results: We identified a cohort of 37 biochemical compounds in plasma that yielded the optimal separation of the irradiated sample groups, with the most correlated metabolites associated with pyrimidine (positively correlated) and tryptophan (negatively correlated) metabolism. The latter were predominantly associated with indole compounds, and there was evidence that these were also correlated between liver and plasma. No evidence of saturation as a function of dose was observed, as has been noted for studies involving metabolite analysis of urine.

Conclusions: Plasma profiling of specific metabolites related to pyrimidine and tryptophan pathways can be used to differentiate whole-body radiation injury and dose response. As the tryptophan-associated indole compounds have their origin in the intestinal microbiome and subsequently the liver, these metabolites particularly represent an attractive marker for radiation injury within blood plasma.
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http://dx.doi.org/10.1016/j.ijrobp.2014.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312583PMC
February 2015

Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors.

Nat Commun 2014 Oct 13;5:5190. Epub 2014 Oct 13.

Department of Medicine, Columbia University, New York, New York 10032, USA.

Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model of insulin signalling, with FoxO1 presiding over glucose production and Srebp-1c regulating lipogenesis, provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO. Liver-specific ablation of three FoxOs (L-FoxO1,3,4) prevents the induction of glucose-6-phosphatase and the repression of glucokinase during fasting, thus increasing lipogenesis at the expense of glucose production. We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose versus lipid metabolism. Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation.
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http://dx.doi.org/10.1038/ncomms6190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197140PMC
October 2014

Advanced mass spectrometry-based multi-omics technologies for exploring the pathogenesis of hepatocellular carcinoma.

Mass Spectrom Rev 2016 May-Jun;35(3):331-49. Epub 2014 Jun 2.

Chongqing University Innovative Drug Research Centre, School of Chemistry and Chemical Engineering, Chongqing, 401331, PR China.

Hepatocellular carcinoma (HCC) is one of the primary hepatic malignancies and is the third most common cause of cancer related death worldwide. Although a wealth of knowledge has been gained concerning the initiation and progression of HCC over the last half century, efforts to improve our understanding of its pathogenesis at a molecular level are still greatly needed, to enable clinicians to enhance the standards of the current diagnosis and treatment of HCC. In the post-genome era, advanced mass spectrometry driven multi-omics technologies (e.g., profiling of DNA damage adducts, RNA modification profiling, proteomics, and metabolomics) stand at the interface between chemistry and biology, and have yielded valuable outcomes from the study of a diversity of complicated diseases. Particularly, these technologies are being broadly used to dissect various biological aspects of HCC with the purpose of biomarker discovery, interrogating pathogenesis as well as for therapeutic discovery. This proof of knowledge-based critical review aims at exploring the selected applications of those defined omics technologies in the HCC niche with an emphasis on translational applications driven by advanced mass spectrometry, toward the specific clinical use for HCC patients. This approach will enable the biomedical community, through both basic research and the clinical sciences, to enhance the applicability of mass spectrometry-based omics technologies in dissecting the pathogenesis of HCC and could lead to novel therapeutic discoveries for HCC.
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http://dx.doi.org/10.1002/mas.21439DOI Listing
December 2016

Hepatic insulin receptor deficiency impairs the SREBP-2 response to feeding and statins.

J Lipid Res 2014 Apr 10;55(4):659-67. Epub 2014 Feb 10.

Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston MA.

The liver plays a central role in metabolism and mediating insulin action. To dissect the effects of insulin on the liver in vivo, we have studied liver insulin receptor knockout (LIRKO) mice. Because LIRKO livers lack insulin receptors, they are unable to respond to insulin. Surprisingly, the most profound derangement observed in LIRKO livers by microarray analysis is a suppression of the cholesterologenic genes. Sterol regulatory element binding protein (SREBP)-2 promotes cholesterologenic gene transcription, and is inhibited by intracellular cholesterol. LIRKO livers show a slight increase in hepatic cholesterol, a 40% decrease in Srebp-2, and a 50-90% decrease in the cholesterologenic genes at the mRNA and protein levels. In control mice, SREBP-2 and cholesterologenic gene expression are suppressed by fasting and restored by refeeding; in LIRKO mice, this response is abolished. Similarly, the ability of statins to induce Srebp-2 and the cholesterologenic genes is lost in LIRKO livers. In contrast, ezetimibe treatment robustly induces Srepb-2 and its targets in LIRKO livers, raising the possibility that insulin may regulate SREBP-2 indirectly, by altering the accumulation or distribution of cholesterol within the hepatocyte. Taken together, these data indicate that cholesterol synthesis is a key target of insulin action in the liver.
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http://dx.doi.org/10.1194/jlr.M043711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966700PMC
April 2014

Alteration of de novo glucose production contributes to fasting hypoglycaemia in Fyn deficient mice.

PLoS One 2013 28;8(11):e81866. Epub 2013 Nov 28.

Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China ; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America.

Previous studies have demonstrated that glucose disposal is increased in the Fyn knockout (FynKO) mice due to increased insulin sensitivity. FynKO mice also display fasting hypoglycaemia despite decreased insulin levels, which suggested that hepatic glucose production was unable to compensate for the increased basal glucose utilization. The present study investigates the basis for the reduction in plasma glucose levels and the reduced ability for the liver to produce glucose in response to gluconeogenic substrates. FynKO mice had a 5-fold reduction in phosphoenolpyruvate carboxykinase (PEPCK) gene and protein expression and a marked reduction in pyruvate, pyruvate/lactate-stimulated glucose output. Remarkably, de novo glucose production was also blunted using gluconeogenic substrates that bypass the PEPCK step. Impaired conversion of glycerol to glucose was observed in both glycerol tolerance test and determination of the conversion of (13)C-glycerol to glucose in the fasted state. α-glycerol phosphate levels were reduced but glycerol kinase protein expression levels were not changed. Fructose-driven glucose production was also diminished without alteration of fructokinase expression levels. The normal levels of dihydroxyacetone phosphate and glyceraldehyde-3-phosphate observed in the FynKO liver extracts suggested normal triose kinase function. Fructose-bisphosphate aldolase (aldolase) mRNA or protein levels were normal in the Fyn-deficient livers, however, there was a large reduction in liver fructose-6-phosphate (30-fold) and fructose-1,6-bisphosphate (7-fold) levels as well as a reduction in glucose-6-phosphate (2-fold) levels. These data suggest a mechanistic defect in the allosteric regulation of aldolase activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081866PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842980PMC
August 2014

SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase.

Mol Cell 2013 Jun;50(5):686-98

Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

Lipid metabolism is tightly controlled by the nutritional state of the organism. Nutrient-rich conditions increase lipogenesis, whereas nutrient deprivation promotes fat oxidation. In this study, we identify the mitochondrial sirtuin, SIRT4, as a regulator of lipid homeostasis. SIRT4 is active in nutrient-replete conditions to repress fatty acid oxidation while promoting lipid anabolism. SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD), an enzyme that produces acetyl CoA from malonyl CoA. Malonyl CoA provides the carbon skeleton for lipogenesis and also inhibits fat oxidation. Mice lacking SIRT4 display elevated MCD activity and decreased malonyl CoA in skeletal muscle and white adipose tissue. Consequently, SIRT4 KO mice display deregulated lipid metabolism, leading to increased exercise tolerance and protection against diet-induced obesity. In sum, this work elucidates SIRT4 as an important regulator of lipid homeostasis, identifies MCD as a SIRT4 target, and deepens our understanding of the malonyl CoA regulatory axis.
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http://dx.doi.org/10.1016/j.molcel.2013.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721068PMC
June 2013

Application of combined omics platforms to accelerate biomedical discovery in diabesity.

Ann N Y Acad Sci 2013 May 9;1287:1-16. Epub 2013 May 9.

Department of Medicine, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine Diabetes Center, Bronx, New York 10461, USA.

Diabesity has become a popular term to describe the specific form of diabetes that develops late in life and is associated with obesity. While there is a correlation between diabetes and obesity, the association is not universally predictive. Defining the metabolic characteristics of obesity that lead to diabetes, and how obese individuals who develop diabetes different from those who do not, are important goals. The use of large-scale omics analyses (e.g., metabolomic, proteomic, transcriptomic, and lipidomic) of diabetes and obesity may help to identify new targets to treat these conditions. This report discusses how various types of omics data can be integrated to shed light on the changes in metabolism that occur in obesity and diabetes.
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http://dx.doi.org/10.1111/nyas.12116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709136PMC
May 2013

Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1.

J Clin Invest 2012 Jul 11;122(7):2417-27. Epub 2012 Jun 11.

Department of Medicine, Division of Endocrinology, Diabetes Research and Training Center, Albert Einstein College of Medicine, New York, NY, USA.

Altered lipid metabolism underlies several major human diseases, including obesity and type 2 diabetes. However, lipid metabolism pathophysiology remains poorly understood at the molecular level. Insulin is the primary stimulator of hepatic lipogenesis through activation of the SREBP-1c transcription factor. Here we identified cyclin-dependent kinase 8 (CDK8) and its regulatory partner cyclin C (CycC) as negative regulators of the lipogenic pathway in Drosophila, mammalian hepatocytes, and mouse liver. The inhibitory effect of CDK8 and CycC on de novo lipogenesis was mediated through CDK8 phosphorylation of nuclear SREBP-1c at a conserved threonine residue. Phosphorylation by CDK8 enhanced SREBP-1c ubiquitination and protein degradation. Importantly, consistent with the physiologic regulation of lipid biosynthesis, CDK8 and CycC proteins were rapidly downregulated by feeding and insulin, resulting in decreased SREBP-1c phosphorylation. Moreover, overexpression of CycC efficiently suppressed insulin and feeding-induced lipogenic gene expression. Taken together, these results demonstrate that CDK8 and CycC function as evolutionarily conserved components of the insulin signaling pathway in regulating lipid homeostasis.
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http://dx.doi.org/10.1172/JCI61462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386818PMC
July 2012

Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression.

Cell Metab 2012 Jun;15(6):873-84

Department of Biochemistry and Biophysics, University of California-San Francisco, and Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.

Dissecting the role of insulin in the complex regulation of triglyceride metabolism is necessary for understanding dyslipidemia and steatosis. Liver insulin receptor knockout (LIRKO) mice show that in the physiological context of feeding, hepatic insulin signaling is not required for the induction of mTORC1, an upstream activator of the lipogenic regulator, SREBP-1c. Feeding induces SREBP-1c mRNA in LIRKO livers, though not to the extent observed in controls. A high fructose diet also partially induces SREBP-1c and lipogenic gene expression in LIRKO livers. Insulin signaling becomes more important in the pathological context of obesity, as knockdown of the insulin receptor in ob/ob mice, a model of Type 2 diabetes, using antisense oligonucleotides, abolishes the induction of SREBP-1c and its targets by obesity and ameliorates steatosis. Thus, insulin-independent signaling pathways can partially compensate for insulin in the induction of SREBP-1c by feeding but the further induction by obesity/Type 2 diabetes is entirely dependent upon insulin.
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http://dx.doi.org/10.1016/j.cmet.2012.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383842PMC
June 2012