Maternal hypercholesterolemia programs dyslipidemia in adult male mouse progeny

in Reproduction

Correspondence should be addressed to T C Rideout; Email: rideout@buffalo.edu

*(J Mathew and S Huang contributed equally to this work)

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As a collection of metabolic abnormalities including inflammation, insulin resistance, hypertension, hormone imbalance, and dyslipidemia, maternal obesity has been well-documented to program disease risk in adult offspring. Although hypercholesterolemia is strongly associated with obesity, less work has examined the programming influence of maternal hypercholesterolemia (MHC) independent of maternal obesity or high-fat feeding. This study was conducted to characterize how MHC per se impacts lipid metabolism in offspring. Female (n = 6/group) C57BL/6J mice were randomly assigned to: (1.) a standard chow diet (Control, CON) or (2.) the CON diet supplemented with exogenous cholesterol (CH) (0.15%, w/w) throughout mating and the gestation and lactation periods. At weaning (postnatal day (PND) 21) and adulthood (PND 84), male offspring were characterized for blood lipid and lipoprotein profile and hepatic lipid endpoints, namely cholesterol and triglyceride (TG) accumulation, fatty acid profile, TG production, and mRNA expression of lipid-regulatory genes. Both newly weaned and adult offspring from CH mothers demonstrated increased very low-density lipoprotein (VLDL) particle number and size and hepatic TG and n-6 polyunsaturated fatty acid accumulation. Further, adult CH offspring exhibited reduced fatty acid synthase (Fasn) and increased diglyceride acyltransferase (Dgat1) mRNA expression. These programming effects appear to be independent of changes in hepatic TG production and postprandial lipid clearance. Study results suggest that MHC, independent of obesity or high-fat feeding, can induce early changes to serum VLDL distribution and hepatic lipid profile that persist into adulthood.

 

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  • AnsteeQMGoldinRD 2006 Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. International Journal of Experimental Pathology 87 116. (https://doi.org/10.1111/j.0959-9673.2006.00465.x)

    • Search Google Scholar
    • Export Citation
  • BlinGLiandMMauduitCChehadeHBenahmedMSimeoniUSiddeekB 2020 Maternal exposure to high-fat diet induces long-term derepressive chromatin marks in the heart. Nutrients 12 E181. (https://doi.org/10.3390/nu12010181)

    • Search Google Scholar
    • Export Citation
  • CamusMCChapmanMJForgezPLaplaudPM 1983 Distribution and characterization of the serum lipoproteins and apoproteins in the mouse, Mus musculus. Journal of Lipid Research 24 12101228.

    • Search Google Scholar
    • Export Citation
  • CarrierBWenSZigourasSBrowneRWLiZPatelMSWilliamsonDLRideoutTC 2014 Alpha-lipoic acid reduces LDL-particle number and PCSK9 concentrations in high-fat fed obese Zucker rats. PLoS ONE 9 e90863. (https://doi.org/10.1371/journal.pone.0090863)

    • Search Google Scholar
    • Export Citation
  • ChuDTMalinowskaEJuraMKozakLP 2017 C57BL/6J mice as a polygenic developmental model of diet-induced obesity. Physiological Reports 5 e13093. (https://doi.org/10.14814/phy2.13093)

    • Search Google Scholar
    • Export Citation
  • ColhounHMThomasonMJMacknessMIMatonSMBetteridgeDJDurringtonPNHitmanGANeilHAfullerJH & Collaborative AtoRvastatin Diabetes Study (CARDS) 2002 Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with type 2 diabetes. Diabetic Medicine 19 201211. (https://doi.org/10.1046/j.1464-5491.2002.00643.x)

    • Search Google Scholar
    • Export Citation
  • DarakiVGeorgiouVPapavasiliouSChalkiadakiGKarahaliouMKoinakiSSarriKVassilakiMKogevinasMChatziL 2015 Metabolic profile in early pregnancy is associated with offspring adiposity at 4 years of age: the rhea pregnancy cohort Crete, Greece. PLoS ONE 10 e0126327. (https://doi.org/10.1371/journal.pone.0126327)

    • Search Google Scholar
    • Export Citation
  • DavisAM 2020 Collateral damage: maternal obesity during pregnancy continues to rise. Obstetrical and Gynecological Survey 75 3949. (https://doi.org/10.1097/OGX.0000000000000734)

    • Search Google Scholar
    • Export Citation
  • DiazECClevesMADicarloMSobikSRRuebelMLThakaliKMSimsCRDajaniNKKrukowskiRABorsheimE et al. 2020 Parental adiposity differentially associates with newborn body composition. Pediatric Obesity 15 e12596. (https://doi.org/10.1111/ijpo.12596)

    • Search Google Scholar
    • Export Citation
  • DumoltJHBrowneRWPatelMSRideoutTC 2019a Malprogramming of hepatic lipid metabolism due to excessive early cholesterol exposure in adult progeny. Molecular Nutrition and Food Research 63 e1800563. (https://doi.org/10.1002/mnfr.201800563)

    • Search Google Scholar
    • Export Citation
  • DumoltJHMaMMathewJPatelMSRideoutTC 2019b Gestational hypercholesterolemia alters fetal hepatic lipid metabolism and microRNA expression in Apo-E-deficient mice. American Journal of Physiology: Endocrinology and Metabolism 317 E831E838. (https://doi.org/10.1152/ajpendo.00138.2019)

    • Search Google Scholar
    • Export Citation
  • FerenceBAGinsbergHNGrahamIRayKKPackardCJBruckertEHegeleRAKraussRMRaalFJSchunkertH et al. 2017 Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. European Heart Journal 38 24592472. (https://doi.org/10.1093/eurheartj/ehx144)

    • Search Google Scholar
    • Export Citation
  • FieldsDADemerathEW 2012 Relationship of insulin, glucose, leptin, IL-6 and TNF-alpha in human breast milk with infant growth and body composition. Pediatric Obesity 7 304312. (https://doi.org/10.1111/j.2047-6310.2012.00059.x)

    • Search Google Scholar
    • Export Citation
  • FreedmanDSOtvosJDJeyarajahEJBarboriakJJAndersonAJWalkerJA 1998 Relation of lipoprotein subclasses as measured by proton nuclear magnetic resonance spectroscopy to coronary artery disease. Arteriosclerosis Thrombosis and Vascular Biology 18 10461053. (https://doi.org/10.1161/01.atv.18.7.1046)

    • Search Google Scholar
    • Export Citation
  • FriedmanJE 2018 Developmental programming of obesity and diabetes in mouse, monkey, and man in 2018: where are we headed? Diabetes 67 21372151. (https://doi.org/10.2337/dbi17-0011)

    • Search Google Scholar
    • Export Citation
  • GaillardRWeltenMOddyWHBeilinLJMoriTAJaddoeVWHuangRC 2016 Associations of maternal prepregnancy body mass index and gestational weight gain with cardio-metabolic risk factors in adolescent offspring: a prospective cohort study. BJOG 123 207216. (https://doi.org/10.1111/1471-0528.13700)

    • Search Google Scholar
    • Export Citation
  • GermanJBSmilowitzJTZivkovicAM 2006 Lipoproteins: when size really matters. Current Opinion in Colloid and Interface Science 11 171183. (https://doi.org/10.1016/j.cocis.2005.11.006)

    • Search Google Scholar
    • Export Citation
  • GoossensGH 2017 The metabolic phenotype in obesity: fat mass, body fat distribution, and adipose tissue function. Obesity Facts 10 207215. (https://doi.org/10.1159/000471488)

    • Search Google Scholar
    • Export Citation
  • GranerETangDRossiSBaronAMigitaTWeinsteinLJLechpammerMHueskenDZimmermanJSignorettiS et al. 2004 The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer Cell 5 253261. (https://doi.org/10.1016/s1535-6108(04)00055-8)

    • Search Google Scholar
    • Export Citation
  • GreenHKehindeO 1974 Sublines of mouse 3T3 cells that accumulate lipid. Cell 1 113116. (https://doi.org/10.1016/0092-8674(74)90126-3)

  • HaeuslerRACamastraSNannipieriMAstiarragaBCastro-PerezJXieDWangLChakravarthyMFerranniniE 2016 Increased bile acid synthesis and impaired bile acid transport in human obesity. Journal of Clinical Endocrinology and Metabolism 101 19351944. (https://doi.org/10.1210/jc.2015-2583)

    • Search Google Scholar
    • Export Citation
  • HudginsLCHellersteinMSeidmanCNeeseRDiakunJHirschJ 1996 Human fatty acid synthesis is stimulated by a eucaloric low fat, high carbohydrate diet. Journal of Clinical Investigation 97 20812091. (https://doi.org/10.1172/JCI118645)

    • Search Google Scholar
    • Export Citation
  • HussenHIPerssonMMoradiT 2015 Maternal overweight and obesity are associated with increased risk of type 1 diabetes in offspring of parents without diabetes regardless of ethnicity. Diabetologia 58 14641473. (https://doi.org/10.1007/s00125-015-3580-1)

    • Search Google Scholar
    • Export Citation
  • IsganaitisEVendittiSMatthewsTJLerinCDemerathEWFieldsDA 2019 Maternal obesity and the human milk metabolome: associations with infant body composition and postnatal weight gain. American Journal of Clinical Nutrition 110 111120. (https://doi.org/10.1093/ajcn/nqy334)

    • Search Google Scholar
    • Export Citation
  • JeyarajahEJCromwellWCOtvosJD 2006 Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clinics in Laboratory Medicine 26 847870. (https://doi.org/10.1016/j.cll.2006.07.006)

    • Search Google Scholar
    • Export Citation
  • JungUJChoiMS 2014 Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. International Journal of Molecular Sciences 15 61846223. (https://doi.org/10.3390/ijms15046184)

    • Search Google Scholar
    • Export Citation
  • JuritschATsaiYTPatelMSRideoutTC 2017 Transcriptional control of enterohepatic lipid regulatory targets in response to early cholesterol and phytosterol exposure in apoE(-/-) mice. BMC Research Notes 10 529. (https://doi.org/10.1186/s13104-017-2859-3)

    • Search Google Scholar
    • Export Citation
  • KanuriGSprussAWagenerbergerSBischoffSCBergheimI 2011 Fructose-induced steatosis in mice: role of plasminogen activator inhibitor-1, microsomal triglyceride transfer protein and NKT cells. Laboratory Investigation 91 885895. (https://doi.org/10.1038/labinvest.2011.44)

    • Search Google Scholar
    • Export Citation
  • KohjimaMEnjojiMHiguchiNKatoMKotohKYoshimotoTFujinoTYadaMYadaRHaradaN et al. 2007 Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. International Journal of Molecular Medicine 20 351358. (https://doi.org/10.3892/ijmm.20.3.351)

    • Search Google Scholar
    • Export Citation
  • KulanuwatSTungtrongchitrRBillingtonDDaviesIG 2015 Prevalence of plasma small dense LDL is increased in obesity in a Thai population. Lipids in Health and Disease 14 30. (https://doi.org/10.1186/s12944-015-0034-1)

    • Search Google Scholar
    • Export Citation
  • LiuJIqbalARaslawskyABrowneRWPatelMSRideoutTC 2016 Influence of maternal hypercholesterolemia and phytosterol intervention during gestation and lactation on dyslipidemia and hepatic lipid metabolism in offspring of Syrian golden hamsters. Molecular Nutrition and Food Research 60 21512160. (https://doi.org/10.1002/mnfr.201600116)

    • Search Google Scholar
    • Export Citation
  • MaedaN 2011 Development of apolipoprotein E-deficient mice. Arteriosclerosis Thrombosis and Vascular Biology 31 19571962. (https://doi.org/10.1161/ATVBAHA.110.220574)

    • Search Google Scholar
    • Export Citation
  • MagalhaesAMatiasIPalmelaIBritoMADiasS 2016 LDL-cholesterol increases the transcytosis of molecules through endothelial monolayers. PLoS ONE 11 e0163988. (https://doi.org/10.1371/journal.pone.0163988)

    • Search Google Scholar
    • Export Citation
  • MagnussenEBVattenLJMyklestadKSalvesenRomundstadPR 2011 Cardiovascular risk factors prior to conception and the length of pregnancy: population-based cohort study. American Journal of Obstetrics and Gynecology 204 526.e1526.e8. (https://doi.org/10.1016/j.ajog.2011.02.016)

    • Search Google Scholar
    • Export Citation
  • Marseille-TremblayCGravelALafondJMounierC 2007 Effect of an enriched cholesterol diet during gestation on fatty acid synthase, HMG-CoA reductase and SREBP-1/2 expressions in rabbits. Life Sciences 81 772778. (https://doi.org/10.1016/j.lfs.2007.07.016)

    • Search Google Scholar
    • Export Citation
  • MaymunahAOKehindeOAbidoyeGOluwatosinA 2014 Hypercholesterolaemia in pregnancy as a predictor of adverse pregnancy outcome. African Health Sciences 14 967973. (https://doi.org/10.4314/ahs.v14i4.28)

    • Search Google Scholar
    • Export Citation
  • MendelsonMMLyassAO’DonnellCJD’AgostinoRBSrLevyD 2016 ASsociation of maternal prepregnancy dyslipidemia with adult offspring dyslipidemia in excess of anthropometric, lifestyle, and genetic factors in the Framingham heart study. JAMA Cardiology 1 2635. (https://doi.org/10.1001/jamacardio.2015.0304)

    • Search Google Scholar
    • Export Citation
  • MillarJSCromleyDAMcCoyMGRaderDJJT BillheimerJT 2005 Determining hepatic triglyceride production in mice: comparison of poloxamer 407 with Triton WR-1339. Journal of Lipid Research 46 2023–2028.

    • Search Google Scholar
    • Export Citation
  • MontoudisABoileauSSimoneauLLafondJ 2003 Impact of an enriched-cholesterol diet on enzymatic cholesterol metabolism during rabbit gestation. Life Sciences 73 14631477. (https://doi.org/10.1016/s0024-3205(03)00436-3)

    • Search Google Scholar
    • Export Citation
  • MorrisonKMAnandSSYusufSAtkinsonSASchulzeKMRao-MelaciniPMcqueenMJMcdonaldSPersadieRHunterB et al. 2013 Maternal and pregnancy related predictors of cardiometabolic traits in newborns. PLoS ONE 8 e55815. (https://doi.org/10.1371/journal.pone.0055815)

    • Search Google Scholar
    • Export Citation
  • NapoliCGlassCKWitztumJLDeutschRD’ArmientoFPPalinskiW 1999 Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet 354 12341241. (https://doi.org/10.1016/S0140-6736(99)02131-5)

    • Search Google Scholar
    • Export Citation
  • NarverudIVan LennepJRChristensenJJVersmissenJGranJMIversenPOAukrustPHalvorsenBUelandTUlvenSM et al. 2015 Maternal inheritance does not predict cholesterol levels in children with familial hypercholesterolemia. Atherosclerosis 243 155160. (https://doi.org/10.1016/j.atherosclerosis.2015.09.014)

    • Search Google Scholar
    • Export Citation
  • NeelandIJPoirierPDespresJP 2018 Cardiovascular and metabolic heterogeneity of obesity: clinical challenges and implications for management. Circulation 137 13911406. (https://doi.org/10.1161/CIRCULATIONAHA.117.029617)

    • Search Google Scholar
    • Export Citation
  • OlkkonenVMBeaslasONissilaE 2012 Oxysterols and their cellular effectors. Biomolecules 2 76103. (https://doi.org/10.3390/biom2010076)

  • OorniKLehtiSSjovallPKovanenPT 2019 Triglyceride-rich lipoproteins as a source of proinflammatory lipids in the arterial wall. Current Medicinal Chemistry 26 17011710. (https://doi.org/10.2174/0929867325666180530094819)

    • Search Google Scholar
    • Export Citation
  • PalmerWKEmesonEEJohnstonTP 1998 Poloxamer 407-induced atherogenesis in the C57BL/6 mouse. Atherosclerosis 136 115–123.

  • PfafflMW 2001 A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Research 29 e45. (https://doi.org/10.1093/nar/29.9.e45)

    • Search Google Scholar
    • Export Citation
  • PrennerSBMulveyCKFergusonJFRickelsMRBhattABReillyMP 2014 Very low density lipoprotein cholesterol associates with coronary artery calcification in type 2 diabetes beyond circulating levels of triglycerides. Atherosclerosis 236 244250. (https://doi.org/10.1016/j.atherosclerosis.2014.07.008)

    • Search Google Scholar
    • Export Citation
  • PuriPBaillieRAWiestMMMirshahiFChoudhuryJCheungOSargeantCContosMJSanyalAJ 2007 A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 46 10811090. (https://doi.org/10.1002/hep.21763)

    • Search Google Scholar
    • Export Citation
  • RideoutTCHardingSVJonesPJ 2010 Consumption of plant sterols reduces plasma and hepatic triglycerides and modulates the expression of lipid regulatory genes and de novo lipogenesis in C57BL/6J mice. Molecular Nutrition and Food Research 54 (Supplement 1) S7S13. (https://doi.org/10.1002/mnfr.201000027)

    • Search Google Scholar
    • Export Citation
  • RideoutTCMovsesianCTsaiYTIqbalARaslawskyAPatelMS 2015 Maternal phytosterol supplementation during pregnancy and lactation modulates lipid and lipoprotein response in offspring of apoE-deficient mice. Journal of Nutrition 145 17281734. (https://doi.org/10.3945/jn.115.215061)

    • Search Google Scholar
    • Export Citation
  • Romejko-WolniewiczELewandowskiZZareba-SzczudlikJCzajkowskiK 2014 BMI of the firstborn offspring at age 12 reflects maternal LDL and HDL cholesterol levels at term pregnancy and postpartum. Journal of Maternal-Fetal and Neonatal Medicine 27 914920. (https://doi.org/10.3109/14767058.2013.846314)

    • Search Google Scholar
    • Export Citation
  • RutledgeJCMullickAEGardnerGGoldbergIJ 2000 Direct visualization of lipid deposition and reverse lipid transport in a perfused artery: roles of VLDL and HDL. Circulation Research 86 768773. (https://doi.org/10.1161/01.res.86.7.768)

    • Search Google Scholar
    • Export Citation
  • SchistermanEFMumfordSLBrowneRWBarrDBChenZLouisGM 2014 Lipid concentrations and couple fecundity: the LIFE study. Journal of Clinical Endocrinology and Metabolism 99 27862794. (https://doi.org/10.1210/jc.2013-3936)

    • Search Google Scholar
    • Export Citation
  • SimWCParkSLeeKYJeYTYinHQChoiYJSungSHParkSJParkHJShinKJ et al. 2014 LXR-alpha antagonist meso-dihydroguaiaretic acid attenuates high-fat diet-induced nonalcoholic fatty liver. Biochemical Pharmacology 90 414424. (https://doi.org/10.1016/j.bcp.2014.06.013)

    • Search Google Scholar
    • Export Citation
  • StahlbergDRudlingMAngelinBBjorkhemIForsellPNilsellKEinarssonK 1997 Hepatic cholesterol metabolism in human obesity. Hepatology 25 14471450. (https://doi.org/10.1002/hep.510250623)

    • Search Google Scholar
    • Export Citation
  • TonstadSJoakimsenOLerenTPOseL 2000 Does maternal or paternal heredity affect carotid atherosclerosis in children with familial hypercholesterolaemia? Acta Paediatrica 89 14901492. (https://doi.org/10.1080/080352500456705)

    • Search Google Scholar
    • Export Citation
  • TsudukiTYamamotoKHatakeyamaYSakamotoY 2016 High dietary cholesterol intake during lactation promotes development of fatty liver in offspring of mice. Molecular Nutrition and Food Research 60 11101117. (https://doi.org/10.1002/mnfr.201500736)

    • Search Google Scholar
    • Export Citation
  • Van Der GraafAVissersMNGaudetDBrissonDSivapalaratnamSRoseboomTJJansenACKasteleinJJHuttenBA 2010 Dyslipidemia of mothers with familial hypercholesterolemia deteriorates lipids in adult offspring. Arteriosclerosis Thrombosis and Vascular Biology 30 26732677. (https://doi.org/10.1161/ATVBAHA.110.209064)

    • Search Google Scholar
    • Export Citation
  • VasileEAntoheFSimionescuMSimionescuN 1989 Transport pathways of beta-VLDL by aortic endothelium of normal and hypercholesterolemic rabbits. Atherosclerosis 75 195210. (https://doi.org/10.1016/0021-9150(89)90177-9)

    • Search Google Scholar
    • Export Citation
  • VersmissenJBotdenIPHuijgenROosterveerDMDefescheJCHeilTCMuntzALangendonkJGSchinkelAFKasteleinJJ et al. 2011 Maternal inheritance of familial hypercholesterolemia caused by the V408M low-density lipoprotein receptor mutation increases mortality. Atherosclerosis 219 690693. (https://doi.org/10.1016/j.atherosclerosis.2011.08.039)

    • Search Google Scholar
    • Export Citation
  • VrinsCLOutRVan SantbrinkPVan Der ZeeAMahmoudiTGroenendijkMHavekesLMVan BerkelTJWillems Van DijkKBiessenEA 2013 Znf202 affects high density lipoprotein cholesterol levels and promotes hepatosteatosis in hyperlipidemic mice. PLoS ONE 8 e57492. (https://doi.org/10.1371/journal.pone.0057492)

    • Search Google Scholar
    • Export Citation
  • YamazakiTSasakiEKakinumaCYanoTMiuraSEzakiO 2005 Increased very low density lipoprotein secretion and gonadal fat mass in mice overexpressing liver DGAT1. Journal of Biological Chemistry 280 2150621514. (https://doi.org/10.1074/jbc.M412989200)

    • Search Google Scholar
    • Export Citation
  • ZhouYZhangXChenLWuJDangHWeiMFanYZhangYZhuYWangN et al. 2008 Expression profiling of hepatic genes associated with lipid metabolism in nephrotic rats. American Journal of Physiology: Renal Physiology 295 F662F671. (https://doi.org/10.1152/ajprenal.00046.2008)

    • Search Google Scholar
    • Export Citation
  • ZhouYRobciucMRWabitschMJuutiALeivonenMEhnholmCYki-JarvinenHOlkkonenVM 2012 OSBP-related proteins (ORPs) in human adipose depots and cultured adipocytes: evidence for impacts on the adipocyte phenotype. PLoS ONE 7 e45352. (https://doi.org/10.1371/journal.pone.0045352)

    • Search Google Scholar
    • Export Citation