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• W2330545139 abstract "Alcohol- and obesity-related liver diseases often coexist. The hepatic lipidomics due to alcohol and obesity interaction is unknown. We characterized the hepatic lipidome due to 1) alcohol consumption in lean and obese mice and 2) obesity and alcohol interactions. In the French-Tsukamoto mouse model, intragastric alcohol or isocaloric dextrose were fed with either chow (lean) or high-fat, high-cholesterol diet (obese). Four groups (lean, lean alcohol, obese, and obese alcohol) were studied. MS was performed for hepatic lipidomics, and data were analyzed. Alcohol significantly increased hepatic cholesteryl esters and diacyl­glycerol in lean and obese but was more pronounced in obese. Alcohol produced contrasting changes in hepatic phospholipids with significant enrichment in lean mice versus significant decrease in obese mice, except phosphatidylglycerol, which was increased in both lean and obese alcohol groups. Most lysophospholipids were increased in lean alcohol and obese mice without alcohol use only. Prostaglandin E2; 5-, 8-, and 11-hydroxyeicosatetraenoic acids; and 9- and 13-hydroxyoctadecadienoic acids were considerably increased in obese mice with alcohol use. Alcohol consumption produced distinct changes in lean and obese with profound effects of obesity and alcohol interaction on proinflammatory and oxidative stress-related eicosanoids. Alcohol- and obesity-related liver diseases often coexist. The hepatic lipidomics due to alcohol and obesity interaction is unknown. We characterized the hepatic lipidome due to 1) alcohol consumption in lean and obese mice and 2) obesity and alcohol interactions. In the French-Tsukamoto mouse model, intragastric alcohol or isocaloric dextrose were fed with either chow (lean) or high-fat, high-cholesterol diet (obese). Four groups (lean, lean alcohol, obese, and obese alcohol) were studied. MS was performed for hepatic lipidomics, and data were analyzed. Alcohol significantly increased hepatic cholesteryl esters and diacyl­glycerol in lean and obese but was more pronounced in obese. Alcohol produced contrasting changes in hepatic phospholipids with significant enrichment in lean mice versus significant decrease in obese mice, except phosphatidylglycerol, which was increased in both lean and obese alcohol groups. Most lysophospholipids were increased in lean alcohol and obese mice without alcohol use only. Prostaglandin E2; 5-, 8-, and 11-hydroxyeicosatetraenoic acids; and 9- and 13-hydroxyoctadecadienoic acids were considerably increased in obese mice with alcohol use. Alcohol consumption produced distinct changes in lean and obese with profound effects of obesity and alcohol interaction on proinflammatory and oxidative stress-related eicosanoids. Alcoholic and nonalcoholic fatty liver diseases (NAFLDs) are two of the most common causes of chronic liver disease worldwide. While alcohol consumption causes alcoholic liver disease (ALD), obesity and insulin resistance underlie the development of NAFLD. ALD remains a leading cause of liver-related mortality in most parts of the world (1Yoon, Y-H., and H. Yi, . 2010. Liver cirrhosis mortality in the United States, 1970–2007. Surveillance report #88. Accessed April 13, 2016, at http://pubs.niaaa.nih.gov/publications/surveillance88/Cirr07.htm.,Google Scholar, 2Rehm J. Samokhvalov A.V. Shield K.D. Global burden of alcoholic liver diseases.J. Hepatol. 2013; 59: 160-168Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar), while NAFLD is a rapidly rising cause of end-stage liver disease and hepatocellular carcinoma in North America (3Rinella M.E. Nonalcoholic fatty liver disease: a systematic review.J. Am. Med. Assoc. 2015; 313: 2263-2273Crossref PubMed Scopus (1495) Google Scholar). Historically, NAFLD was defined as a condition with a spectrum of liver histology similar to that seen in ALD but occurred in the absence of alcohol consumption in amounts that was considered harmful (4Ludwig J. Viggiano T.R. McGill D.B. Oh B.J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.Mayo Clin. Proc. 1980; 55: 434-438PubMed Google Scholar). Consequently, in studies in NAFLD, an alcohol consumption threshold below 20–30 g/day has been used (5Sanyal, A. J., N. Chalasani, K. V. Kowdley, A. McCullough, A. M. Diehl, N. M. Bass, B. A. Neuschwander-Tetri, J. E. Lavine, J. Tonascia, A. Unalp, ; NASH CRN. 2010. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362: 1675–1685.Google Scholar, 6Sanyal A.J. Brunt E.M. Kleiner D.E. Kowdley K.V. Chalasani N. Lavine J.E. Ratziu V. McCullough A. Endpoints and clinical trial design for nonalcoholic steatohepatitis.Hepatology. 2011; 54: 344-353Crossref PubMed Scopus (518) Google Scholar, 7Chalasani, N., Z. Younossi, J. E. Lavine, A. M. Diehl, E. M. Brunt, K. Cusi, M. Charlton, and A. J. Sanyal, ; American Gastroenterological Association; American Association for the Study of Liver Diseases; American College of Gastroenterology. 2012. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 142: 1592–1609.Google Scholar). Conversely, the development of ALD is considered to require sustained consumption of >60 g of alcohol daily over many years (8Worner T.M. Lieber C.S. Perivenular fibrosis as precursor lesion of cirrhosis.J. Am. Med. Assoc. 1985; 254: 627-630Crossref PubMed Scopus (142) Google Scholar, 9Teli M.R. Day C.P. Burt A.D. Bennett M.K. James O.F. Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver.Lancet. 1995; 346: 987-990Abstract PubMed Scopus (409) Google Scholar, 10O'Shea, R. S., S. Dasarathy, and A. J. McCullough, ; Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. 2010. Alcoholic liver disease. Hepatology. 51: 307–328.Google Scholar). ALD and NAFLD are thus considered to represent distinct conditions separated by the amount of alcohol consumed despite having similar liver histology. Implicit in this concept is that these conditions have a distinct molecular and physiological basis for disease development. Over the past decade, these apparently clean distinctions have become increasingly blurred. About two-thirds of the adult American population is obese and overweight (11Ogden C.L. Carroll M.D. Kit B.K. Flegal K.M. Prevalence of childhood and adult obesity in the United States, 2011-2012.J. Am. Med. Assoc. 2014; 311: 806-814Crossref PubMed Scopus (6306) Google Scholar). At the same time, alcohol use is widely prevalent in the United States with 87.6% of people ages 18 or older reporting alcohol consumption at some point in their lifetime; of these 71% consumed an alcoholic drink in the past year, and 56.3% consumed alcohol within the past month (12National Institute on Alcohol Abuse and Alcoholism. 2015. Alcohol facts and statistics. Accessed July 15, 2015, at http://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/alcohol-facts-and-statistics.,Google Scholar). It is therefore no surprise that alcohol use and obesity often coexist. While clinical data indicate that obese individuals who consume alcohol are more likely to develop fatty liver disease (13Loomba R. Bettencourt R. Barrett-Connor E. Synergistic association between alcohol intake and body mass index with serum alanine and aspartate aminotransferase levels in older adults: the Rancho Bernardo Study.Aliment. Pharmacol. Ther. 2009; 30: 1137-1149Crossref PubMed Scopus (75) Google Scholar), there is a paucity of literature on how these risk factors interact to contribute to the pathogenesis of the underlying liver disease. Both ALD and NAFLD are characterized by steatosis, and lipotoxicity is believed to contribute to their pathogenesis (14Gao B. Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets.Gastroenterology. 2011; 141: 1572-1585Abstract Full Text Full Text PDF PubMed Scopus (1330) Google Scholar, 15Malhi H. Bronk S.F. Werneburg N.W. Gores G.J. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis.J. Biol. Chem. 2006; 281: 12093-12101Abstract Full Text Full Text PDF PubMed Scopus (569) Google Scholar). Biologically active lipids are important mediators of multiple physiological and pathologic processes. Perturbed lipid homeostasis can lead to steatosis, inflammation, and fibrotic processes that are significant pathophysiological determinants of disease progression and severity in both NAFLD and ALD (16Donnelly K.L. Smith C.I. Schwarzenberg S.J. Jessurun J. Boldt M.D. Parks E.J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.J. Clin. Invest. 2005; 115: 1343-1351Crossref PubMed Scopus (2412) Google Scholar, 17Puri P. Baillie R.A. Wiest M.M. Mirshahi F. Choudhury J. Cheung O. Sargeant C. Contos M.J. Sanyal A.J. A lipidomic analysis of nonalcoholic fatty liver disease.Hepatology. 2007; 46: 1081-1090Crossref PubMed Scopus (915) Google Scholar, 18Puri P. Wiest M.M. Cheung O. Mirshahi F. Sargeant C. Min H.K. Contos M.J. Sterling R.K. Fuchs M. Zhou H. et al.The plasma lipidomic signature of nonalcoholic steatohepatitis.Hepatology. 2009; 50: 1827-1838Crossref PubMed Scopus (472) Google Scholar, 19Min H.K. Kapoor A. Fuchs M. Mirshahi F. Zhou H. Maher J. Kellum J. Warnick R. Contos M.J. Sanyal A.J. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.Cell Metab. 2012; 15: 665-674Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar, 20Liangpunsakul S. Sozio M.S. Shin E. Zhao Z. Xu Y. Ross R.A. Zeng Y. Crabb D.W. Inhibitory effect of ethanol on AMPK phosphorylation is mediated in part through elevated ceramide levels.Am. J. Physiol. Gastrointest. Liver Physiol. 2010; 298: G1004-G1012Crossref PubMed Scopus (69) Google Scholar, 21Fernando H. Bhopale K.K. Kondraganti S. Kaphalia B.S. Shakeel Ansari G.A. Lipidomic changes in rat liver after long-term exposure to ethanol.Toxicol. Appl. Pharmacol. 2011; 255: 127-137Crossref PubMed Scopus (53) Google Scholar, 22Gorden D.L. Myers D.S. Ivanova P.T. Fahy E. Maurya M.R. Gupta S. Min J. Spann N.J. McDonald J.G. Kelly S.L. et al.Biomarkers of NAFLD progression: a lipidomics approach to an epidemic.J. Lipid Res. 2015; 56: 722-736Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar). Most studies have, however, focused on either NAFLD or ALD, and the interactions between obesity and alcohol consumption on lipid metabolism have not been previously described. Advances in analytical methodology now permit simultaneous quantitative measurement of individual lipid species across all major lipid classes from biological samples. This allows an unbiased analysis of the changes in lipid metabolism from the profile of such lipid species measured by these high-throughput techniques. The objective of the current studies was to evaluate the effects of obesity and alcohol consumption on the hepatic lipidome in C57B/6 mice. The specific aims of the study were to characterize 1) the effects of alcohol consumption on hepatic lipidome in lean and obese mice and 2) the changes in hepatic lipidome due to obesity and alcohol interactions. This was accomplished by comparison of the hepatic lipidome in 1) lean mice fed chow diet or an isocaloric chow diet and alcohol with alcohol administration via intragastric (iG) gavage (French-Tsukamoto model) (23Ueno A. Lazaro R. Wang P.Y. Higashiyama R. Machida K. Tsukamoto H. Mouse intragastric infusion (iG) model.Nat. Protoc. 2012; 7: 771-781Crossref PubMed Scopus (69) Google Scholar); 2) obese mice fed a high-fat, high-cholesterol diet (HFCD) or isocaloric diet and alcohol; 3) obese mice versus lean mice fed an HFCD or chow diet, respectively; and 4) obese versus lean mice fed alcohol-containing diets. The studies were performed in C57B/6 mice. These mice have been used for studies in both diet-induced obesity and alcohol previously (24Lazaro R. Wu R. Lee S. Zhu N.L. Chen C.L. French S.W. Xu J. Machida K. Tsukamoto H. Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice.Hepatology. 2015; 61: 129-140Crossref PubMed Scopus (85) Google Scholar). Initially, 8-week-old male C57B/6 mice were fed an HFCD containing 20% calories from lard and 1% cholesterol (Dyets Inc., #180724) or chow diet ad libitum for 2 weeks as described previously (23Ueno A. Lazaro R. Wang P.Y. Higashiyama R. Machida K. Tsukamoto H. Mouse intragastric infusion (iG) model.Nat. Protoc. 2012; 7: 771-781Crossref PubMed Scopus (69) Google Scholar). The iG catheter was then implanted, and iG feeding was initiated for 8 weeks that provided 60% of total daily caloric intake while the mice consumed remaining 40% calories via ad libitum intake of chow or HFCD (23Ueno A. Lazaro R. Wang P.Y. Higashiyama R. Machida K. Tsukamoto H. Mouse intragastric infusion (iG) model.Nat. Protoc. 2012; 7: 771-781Crossref PubMed Scopus (69) Google Scholar). The iG feeding delivered a high-fat liquid diet (36% calories from corn oil) plus ethanol (26∼27 g/kg/day) (CHOW+Alc, HFCD+Alc) or isocaloric dextrose (CHOW+Cont, HFCD+Cont). Thus, four groups of mice were studied: 1) lean mice (i.e., mice fed a chow diet alone and iG administration of isocaloric diet); 2) lean-alcohol (LA) mice (i.e., mice fed a chow diet and iG administration of alcohol); 3) obese mice (i.e., mice fed an HFCD ad libitum with isocaloric diet); and 4) obese-alcohol (OA) mice (i.e., mice fed HFCD ad libitum with iG alcohol). On the last day of the experiments, the animals were anesthetized, venous was blood collected, and then the animals were euthanized. The entire liver and spleen was removed and weighed, and livers were processed for analyses including lipidomic analysis and hematoxylin and eosin and reticulin staining. Plasma aspartate aminotransferase and alanine aminotransferase were analyzed by a kinetic assay, and albumin and bilirubin levels by autoanalyzer. The animal research was conducted in conformity with the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals, incorporated in the Institute for Laboratory Animal Research (ILAR) Guide for Care and Use of Laboratory Animals. The animal protocol for this study was approved by the Institutional Animal Care and Use Committee at the University of Southern California. Lipid extraction, MS-based lipid detection, and data analysis were performed by Zora Biosciences Oy (25Jung H.R. Sylvänne T. Koistinen K.M. Tarasov K. Kauhanen D. Ekroos K. High throughput quantitative molecular lipidomics.Biochim. Biophys. Acta. 2011; 1811: 925-934Crossref PubMed Scopus (134) Google Scholar). The liver tissue samples (∼50–150 µg) were weighted, pulverized with CP02 CryoPrep Dry Pulverization System (Covaris Inc., Woburn, MA), and resuspended in ice-cold methanol (LC/MS grade; Sigma-Aldrich GmbH, Steinheim, Germany) containing 0.1% butyl-hydroxy-toluene (≥99.0%; Sigma-Aldrich) in a concentration of 100 mg/ml. Eicosanoids were extracted from 50 µl of liver homogenate using solid-phase extraction (SPE; Strata-X 33u Polymeric RP 96-well Plate, 60 mg/well; Phenomenex, Torrance, CA) as described in Ref. (26Deems R. Buczynski M.W. Bowers-Gentry R. Harkewicz R. Dennis E.A. Detection and quantitation of eicosanoids via high performance liquid chromatography-electrospray ionization-mass spectrometry.Methods Enzymol. 2007; 432: 59-82Crossref PubMed Scopus (139) Google Scholar). Prior to extraction, known amounts of isotope-labeled standards (arachidonic acid (AA)-d8, docosahexaenoic acid-d5, eicosapentaenoic acid-d5, prostaglandin D2 (PGD2)-d4, thromboxane B2-d4, leukotriene B4-d4, lipoxin A4-d5, 8,9-dihydroxyeicosatrienoic acid (DHET)-d11, 5-HETE-d8, 12-HETE-d8, 13-hydroxy-9,11-octadecadienoic acid (13-HODE)-d4, and 9-hydroxy-10,12-octadecadienoic acid (9-HODE)-d4; Cayman Chemicals, Ann Arbor, MI) were included as synthetic internal standards. Samples were loaded to SPE plate after conditioning the plate with methanol and ultrapure water (both LC/MS grade; Sigma Aldrich). The SPE wells were washed with 35% methanol prior to elution with acetonitrile (LC/MS grade; Sigma-Aldrich). The samples were then evaporated under nitrogen until dry and reconstituted in methanol followed by addition of external standard mixture [15(S)-HETE-d8 and PGD2-d9; Cayman Chemicals]. In shotgun lipidomics, lipids were extracted from 10 µl of liver homogenate using a modified Folch lipid extraction, using chloroform (HPLC grade), methanol, and acetic acid (both LC/MS grade) for liquid-liquid extraction (27Ståhlman M. Ejsing C.S. Tarasov K. Perman J. Borén J. Ekroos K. High-throughput shotgun lipidomics by quadrupole time-of-flight mass spectrometry.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2009; 877: 2664-2672Crossref PubMed Scopus (173) Google Scholar) performed on 96-well plates using a Hamilton Microlab Star system (Hamilton Robotics AB, Kista, Sweden). All solvents were purchased from Sigma-Aldrich. Samples were spiked with known amounts of lipid-class specific, nonendogeneous synthetic internal standards. After lipid extraction, samples were reconstituted in chloroform-methanol (1:2, v/v), and synthetic external standards were postextract spiked to the extracts (28Heiskanen L.A. Suoniemi M. Ta H.X. Tarasov K. Ekroos K. Long-term performance and stability of molecular shotgun lipidomic analysis of human plasma samples.Anal. Chem. 2013; 85: 8757-8763Crossref PubMed Scopus (61) Google Scholar). Quality controls (QCs) were prepared along with the samples for both eicosanoid and shotgun lipidomic analyses to monitor the extraction and MS performance. In addition, calibration lines were prepared to determine the linear dynamic range of the MS analyses. QCs and calibration lines were prepared in reference liver matrix. Eicosanoids were analyzed on a hybrid triple quadrupole/linear ion trap mass spectrometer (5500 QTRAP; AB Sciex, Concord, Canada) equipped with an ultra-high-pressure liquid chromatography system (CTC HTC PAL autosampler, CTC Analytics AG, Zwingen, Switzerland; and Rheos Allegro pump, Flux Instruments AG, Basel, Switzerland) using multiple reaction monitoring (MRM)-based method in negative ion mode as in Ref. (26Deems R. Buczynski M.W. Bowers-Gentry R. Harkewicz R. Dennis E.A. Detection and quantitation of eicosanoids via high performance liquid chromatography-electrospray ionization-mass spectrometry.Methods Enzymol. 2007; 432: 59-82Crossref PubMed Scopus (139) Google Scholar). Eicosanoids were identified based on their retention times and compound-specific MRM ion pairs, and quantified by normalizing to the respective isotope-labeled internal standard and the sample amount. Data were processed using Multiquant (AB Sciex) and SAS (SAS Institute Inc., Cary, NC) software. In shotgun lipidomics, lipid extracts were analyzed on a hybrid triple quadrupole/linear ion trap mass spectrometer (QTRAP 5500) equipped with a robotic nanoflow ion source (NanoMate; Advion Biosciences Inc., Ithaca, NY) as described (28Heiskanen L.A. Suoniemi M. Ta H.X. Tarasov K. Ekroos K. Long-term performance and stability of molecular shotgun lipidomic analysis of human plasma samples.Anal. Chem. 2013; 85: 8757-8763Crossref PubMed Scopus (61) Google Scholar). Molecular lipids were analyzed in both positive and negative ion modes using multiple precursor ion scanning-based methods (29Ekroos K. Chernushevich I.V. Simons K. Shevchenko A. Quantitative profiling of phospholipids by multiple precursor ion scanning on a hybrid quadrupole time-of-flight mass spectrometer.Anal. Chem. 2002; 74: 941-949Crossref PubMed Scopus (256) Google Scholar, 30Ekroos K. Ejsing C.S. Bahr U. Karas M. Simons K. Shevchenko A. Charting molecular composition of phosphatidylcholines by fatty acid scanning and ion trap MS3 fragmentation.J. Lipid Res. 2003; 44: 2181-2192Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar). The molecular lipid species were identified and quantified in absolute [cholesteryl ester (CE), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine, lyso-PC (LPC), lyso-PE (LPE), diacylglycerol (DAG), SM] or semiabsolute [phosphatidylinositol (PI), PC-O, PC-P, PE-O, PE-P] amounts (31Ejsing C.S. Duchoslav E. Sampaio J. Simons K. Bonner R. Thiele C. Ekroos K. Shevchenko A. Automated identification and quantification of glycerophospholipid molecular species by multiple precursor ion scanning.Anal. Chem. 2006; 78: 6202-6214Crossref PubMed Scopus (329) Google Scholar) by normalizing to their respective synthetic internal standard and the sample amount. Data processing was performed by LipidView (AB Sciex) and SAS. The concentrations of all lipids are presented as picomoles per microgram wet tissue weight. Missing concentrations that were below the detection limit were substituted with a value that is half of the lowest observed concentration within the group. Groups that had only substituted values (variance = 0) were excluded from the testing. Unpaired Student's t-test was performed to log-transformed lipid concentrations. Testing was performed only if study groups had three or more observations. The results of the analysis included group averages, relative change between the group averages, and P value (from log scale). Changes are expressed as percentage changes of average concentrations of a group and calculated as follows: %Change = 100 × [(average(Group 2) – average(Group 1)]/average(Group 1). Data were analyzed using Tableau 9 and GraphPad Prism 6 software. A total of six to nine mice were studied in each of the four groups noted above. The mice on chow diet had no significant change in weight without and with alcohol use (lean and LA groups). In contrast, compared with lean mice, HFCD-fed mice gained weight compared with baseline values: 21.5% without alcohol (obese, P = 0.01) and 7.5% with alcohol (OA, P = 0.03). This combination of diet and alcohol use mimicked the common human phenotype and resulted in biochemical and histological changes similar to human ALD as previously reported (24Lazaro R. Wu R. Lee S. Zhu N.L. Chen C.L. French S.W. Xu J. Machida K. Tsukamoto H. Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice.Hepatology. 2015; 61: 129-140Crossref PubMed Scopus (85) Google Scholar). A detailed lipidomic data for all four groups (mean ± SD) are provided in supplementary Tables 1–7. To determine whether alcohol feeding led to similar or differential changes in the context of background obesity, the hepatic lipidome was compared in lean mice with or without alcohol feeding and in mice fed an HFCD with or without alcohol. The key hepatic lipidome findings are described below. Alcohol significantly increased total hepatic CE content in lean mice (LA vs. lean, +214% difference; P = 0.009) (Fig. 1A). This increase was even more pronounced in obese mice (OA vs. obese, +505% difference; P = 0.003). Interestingly, the CE increase in obese mice was driven by a marked increase in several saturated and mono- and polyunsaturated fatty acid species in CE. Alcohol use also produced significantly increased total hepatic DAG concentration in both lean (LA vs. lean, mean relative change +96%; P = 0.0009) and obese mice (OA vs. obese, mean relative change +35%; P = 0.02). The relative effect was, however, more pronounced in lean mice. Further, hepatic DAGs were enriched in mono- and polyunsaturated fatty acids at the C2 position, more prominently in the lean mice (Fig. 1B).Fig. 1Distinct effects of alcohol consumption in lean and obese mice. Total and lipid species within CE (A) and DAG (B). C: Alcohol increased hepatic phospholipids (PLs) in lean and depleted PLs in obese, most notably in PC. Total PG was significantly higher in OA versus obese compared with LA versus lean. D: Hepatic lyso-PLs in lean and obese. L, lean; O, obese. Red bar indicates increase; blue bar indicates decrease. * P < 0.05; ** P < 0.01; *** P < 0.001.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Alcohol intake significantly increased several classes of phospholipids in lean mice (Fig. 1C). Specifically, total hepatic PC content was higher in LA versus lean mice (+24.5% difference, P = 0.04). Similarly, total hepatic PE (+38% difference, P = 0.001) and total hepatic PI (+32.5% difference, P = 0.01) were also significantly increased in LA versus lean mice. In contrast, alcohol significantly decreased total hepatic PC (27% decrease, P = 0.002) in OA versus obese mice. While phosphatidylglycerol (PG) increased with alcohol consumption in both lean and obese mice, the effect size was substantially greater (P < 0.05) in OA mice. Alcohol consumption also had opposing effects on the levels of lysophospholipids in lean versus obese mice (Fig. 1D). LA mice demonstrated significantly elevated total hepatic LPE (+90% difference, P = 0.0004), lyso-PG (LPG; +119% difference, P = 0.002), and lyso-PI (LPI; +165% difference, P = 0.002) compared with lean mice. On the other hand, total hepatic LPC (−52% difference, P = 0.002) and LPE (−37% difference, P = 0.01) were reduced in OA versus obese mice. The directionality of these hepatic lysophospholipid changes indicates that alcohol produces distinct effects in the setting of background obesity versus a lean state. Several proinflammatory cyclooxygenase (COX) metabolites were increased in both lean and obese mice fed alcohol (Fig. 2A). Specifically, total hepatic prostaglandin E2 (PGE2) content was markedly elevated in LA versus lean mice (+241% difference, P = 0.01). These changes were further greatly enhanced in the setting of obesity with OA mice having a markedly greater increase in PGE2 versus obese mice (+569% difference, P = 0.0001). Also, alcohol use in obese mice resulted in pronounced increase in total hepatic PGD2 and prostaglandin F2α (PGF2α) compared with lean mice.Fig. 2Distinct alcohol effects on eicosanoids in lean and obese mice. COX (PGE2, PGD2, and PGF2-α) (A), LOX (HEPE and HETE) (B), 8-HETE (C), and CYP450 pathway (EETs and DHETs) and EPA changes with alcohol (D). E: Nonenzymatic oxidative stress markers 9- and 13-HODEs, and 11-HETE. EET, epoxyeicosatrienoic acid; HEPE, hydroxyeicosapentaenoic acid. Red bar indicates increase; blue bar indicates decrease. * P < 0.05; ** P < 0.01; *** P < 0.001.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Interestingly, alcohol consumption produced varying effects in lean mice versus mice with obesity with respect to lipoxygenase (LOX) metabolites (Fig. 2B). Specifically, OA versus obese mice had significantly increased hepatic 5-HEPE (+125% difference, P = 0.02), 12-HEPE (+531.7% increase, P = 0.0003), and 15-HEPE (+95.6% increase, P = 0.01). Notably, alcohol use in obese mice produced markedly increased 5-HETE, 12-HETE, and 15-HETE in contrast to lean mice where a modest decrease in these LOX metabolites was noted. Also, alcohol use in obese mice remarkably increased total hepatic 8-HETE (OA vs. obese, +273% difference; P = 0.003) without any significant change in the lean mice (Fig. 2C). Among the cytochrome P450 (CYP450) metabolites (Fig. 2D), alcohol use resulted in concordant changes for obese and lean groups with the exception of 5,6-EET and 11,12-EET, which were markedly increased in OA versus obese mice but not in LA versus lean mice. A similar divergent effect of alcohol was also noticeable for total EPA with significantly increased hepatic content (+90% difference, P < 0.05) in LA versus lean mice but not in OA versus obese mice. Further, DHETs also had concordant decrease with alcohol use in both obese and lean mice. Specifically, both 11,12-DHETs (LA vs. lean, −52.5% difference, P < 0.001; OA vs. obese, −55% difference, P < 0.001) and 14,15-DHETs (LA vs. lean, −59% difference, P = 0.0001; OA vs. obese, −76% difference, P = 0.00001) were significantly decreased. Additionally, markedly decreased 5,6-DHET (−48% difference, P = 0.01) and 8,9-DHET (−46% difference, P = 0.008) were observed in OA versus obese mice only. Alcohol use also induced marked hepatic changes in the nonenzymatic oxidative metabolites (Fig. 2E). The total hepatic 9-HODE (+95% difference, P = 0.04) and 13-HODE (+83% difference, P = 0.02) levels were markedly elevated in LA versus lean mice. Similar changes were also noted in OA versus obese mice. The interactions between obesity on the hepatic lipidomic response to alcohol consumption were evaluated by comparison of the hepatic lipidome in OA versus LA mice and relating them to changes seen in obese versus lean mice. Hepatic CE (Fig. 3A) and DAG (Fig. 3B) were both increased by obesity, and these changes were sustained with alcohol consumption. Together with the data shown in “Alcohol Use Increased Hepatic CEs and DAG,” these data demonstrate that both obesity and alcohol consumption increased hepatic CE accumulation as well as DAGs. The HFCD induced obesity with and without alcohol use and resulted in prominent increase in MUFA and PUFA in both CE and DAGs.Fig. 3Alcohol and obesity interaction related hepatic lipidome. Changes in CE (A) and DAG (B). C: Divergent effects of alcohol in hepatic phospholipids (PC, PE, PG, and PI). D: Hepatic lysophospholipids. Red bar indicates increase; blue bar indicates decrease. * P < 0.05; ** P < 0.01; *** P < 0.001." @default.
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• W2330545139 date "2016-06-01" @default.
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• W2330545139 title "Alcohol produces distinct hepatic lipidome and eicosanoid signature in lean and obese" @default.
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