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• W2120634442 abstract "Human apolipoprotein B (apoB) transgenic (HuBTg) mouse strains were used to assess genetic effects on the response to fish oil (FO), a source of n-3 fatty acids. A congenic HuBTg strain of the C57BL/6 (B6) background and six F1 HuBTg strains were fed a FO for 2 weeks. Different responses of plasma lipid levels to FO were observed among these strains. In particular, plasma apoB levels changed minimally in FO-fed male B6 HuBTg mice, but increased markedly (∼40%) in FO-fed male FVB/NJ (FVB) × B6 F1 HuBTg mice. These strain differences were determined mainly by hepatic apoB secretion rates and were likely regulated by posttranscriptional mechanisms. In addition, plasma triglyceride (TG) levels were reduced (14%) in FO-fed B6 mice, but not in FVB × B6 mice. These strain differences were determined mainly by TG secretion rates, but were not due to differences in hepatic lipogenesis. Hepatic mRNA levels of acyl-CoA oxidase, reflective of peroxisomal β-oxidation rate, were increased in FO-fed B6 but not in FVB × B6 mice, which could account for the difference in TG secretion rates.In summary, differential effects of FO on plasma apoB and TG levels in B6 and FVB × B6 HuBTg mice were associated with strain differences in hepatic apoB and TG secretion and in peroxisomal β-oxidation. Human apolipoprotein B (apoB) transgenic (HuBTg) mouse strains were used to assess genetic effects on the response to fish oil (FO), a source of n-3 fatty acids. A congenic HuBTg strain of the C57BL/6 (B6) background and six F1 HuBTg strains were fed a FO for 2 weeks. Different responses of plasma lipid levels to FO were observed among these strains. In particular, plasma apoB levels changed minimally in FO-fed male B6 HuBTg mice, but increased markedly (∼40%) in FO-fed male FVB/NJ (FVB) × B6 F1 HuBTg mice. These strain differences were determined mainly by hepatic apoB secretion rates and were likely regulated by posttranscriptional mechanisms. In addition, plasma triglyceride (TG) levels were reduced (14%) in FO-fed B6 mice, but not in FVB × B6 mice. These strain differences were determined mainly by TG secretion rates, but were not due to differences in hepatic lipogenesis. Hepatic mRNA levels of acyl-CoA oxidase, reflective of peroxisomal β-oxidation rate, were increased in FO-fed B6 but not in FVB × B6 mice, which could account for the difference in TG secretion rates. In summary, differential effects of FO on plasma apoB and TG levels in B6 and FVB × B6 HuBTg mice were associated with strain differences in hepatic apoB and TG secretion and in peroxisomal β-oxidation. Epidemiological studies have demonstrated an inverse correlation between fish consumption and the incidence of coronary heart disease (1Kromhout D. Bosschieter E.B. de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease.N. Engl. J. Med. 1985; 312: 1205-1209Google Scholar, 2Dolecek T.A. Granditis G. Dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial (MRFIT).World Rev. Nutr. Diet. 1991; 66: 205-216Google Scholar, 3Daviglus M.L. Stamler J. Orencia A.J. Dyer A.R. Liu K. Greenland P. Walsh M.K. Morris D. Shekelle R.B. Fish consumption and the 30-year risk of fatal myocardial infarction.N. Engl. J. Med. 1997; 336: 1046-1053Google Scholar, 4Hu F.B. Bronner L. Willett W.C. Stampfer M.J. Rexrode K.M. Albert C.M. Hunter D. Manson J.E. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women.JAMA. 2002; 287: 1815-1821Google Scholar). Dietary fish oil (FO) enriches hepatic plasma and microsomal membranes with n-3 fatty acids. This enrichment subsequently alters hormone binding to cell-surface receptors and affects intracellular signal transduction, which in turn modifies lipid metabolism [reviewed in ref. (5Jump D.B. Clarke S.D. Regulation of gene expression by dietary fat.Annu. Rev. Nutr. 1999; 19: 63-90Google Scholar)]. These fatty acids also affect nuclear mechanisms that change the expression of various genes encoding enzymes involved in lipid metabolism (5Jump D.B. Clarke S.D. Regulation of gene expression by dietary fat.Annu. Rev. Nutr. 1999; 19: 63-90Google Scholar). Dietary n-3 fatty acids exert pleiotrophic effects, including triglyceride (TG)-lowering action, which reduce many cardiovascular risk factors in humans (6Harris W.S. n-3 fatty acids and lipoproteins: comparison of results from human and animal studies.Lipids. 1996; 31: 243-252Google Scholar, 7Semplicini A. Valle R. Fish oils and their possible role in the treatment of cardiovascular diseases.Pharmacol. Ther. 1994; 61: 385-397Google Scholar, 8Parks J.S. Rudel L.L. Effect of fish oil on atherosclerosis and lipoprotein metabolism.Atherosclerosis. 1990; 84: 83-94Google Scholar). N-3 fatty acids reduce plasma TGs by inhibition of VLDL synthesis in the liver and/or stimulation of their catabolism (6Harris W.S. n-3 fatty acids and lipoproteins: comparison of results from human and animal studies.Lipids. 1996; 31: 243-252Google Scholar, 9Nestel P.J. Effects of N-3 fatty acids on lipid metabolism.Annu. Rev. Nutr. 1990; 10: 149-167Google Scholar). N-3 fatty acids reduce microsomal fatty acid synthesis and increase peroxisomal and mitochondrial oxidation by altering the expression of genes involved in their biosynthesis (9Nestel P.J. Effects of N-3 fatty acids on lipid metabolism.Annu. Rev. Nutr. 1990; 10: 149-167Google Scholar). It is thought that these integrated mechanisms result in the reduction of hepatic VLDL TG synthesis. In humans, a decrease of VLDL apoB flux by FO has been documented (10Nestel P.J. Connor W.E. Reardon M.F. Connor S. Wong S. Boston R. Suppression by diets rich in fish oil of very low density lipoprotein production in man.J. Clin. Invest. 1984; 74: 82-89Scopus (459) Google Scholar). The inhibition of apoB secretion by n-3 fatty acids has been shown to result from an increase in intracellular apoB degradation in cultured cells, including a human hepatoma cell line (HepG2) and rat and hamster primary hepatocytes (11Wong S.H. Fisher E.A. Marsh J.B. Effects of eicosapentaenoic and docosahexaenoic acids on apoprotein B mRNA and secretion of very low density lipoprotein in HepG2 cells.Arteriosclerosis. 1989; 9: 836-841Google Scholar, 12Wong S. Nestel P.J. Eicosapentaenoic acid inhibits the secretion of triacylglycerol and of apoprotein B and the binding of LDL in Hep G2 cells.Atherosclerosis. 1987; 64: 139-146Google Scholar, 13Wang H. Chen X. Fisher E.A. N-3 fatty acids stimulate intracellular degradation of apoprotein B in rat hepatocytes.J. Clin. Invest. 1993; 91: 1380-1389Google Scholar, 14Ribeiro A. Mangeney M. Cardot P. Loriette C. Rayssiguier Y. Chambaz J. Bereziat G. Effect of dietary fish oil and corn oil on lipid metabolism and apolipoprotein gene expression by rat liver.Eur. J. Biochem. 1991; 196: 499-507Google Scholar, 15Brown A.M. Baker P.W. Gibbons G.F. Changes in fatty acid metabolism in rat hepatocytes in response to dietary n-3 fatty acids are associated with changes in the intracellular metabolism and secretion of apolipoprotein B-48.J. Lipid Res. 1997; 38: 469-481Google Scholar, 16Kendrick J.S. Higgins J.A. Dietary fish oils inhibit early events in the assembly of very low density lipoproteins and target apoB for degradation within the rough endoplasmic reticulum of hamster hepatocytes.J. Lipid Res. 1999; 40: 504-514Google Scholar, 17Fisher E.A. Pan M. Chen X. Wu X. Wang H. Jamil H. Sparks J.D. Williams K.J. The triple threat to nascent apolipoprotein B. Evidence for multiple, distinct degradative pathways.J. Biol. Chem. 2001; 276: 27855-27863Google Scholar). However, the effects of n-3 fatty acids on plasma LDL cholesterol levels in humans are less consistent (6Harris W.S. n-3 fatty acids and lipoproteins: comparison of results from human and animal studies.Lipids. 1996; 31: 243-252Google Scholar). In some reports, increased plasma LDL levels produced by n-3 fatty acids have been documented (18Harris W.S. Fish oils and plasma lipid and lipoprotein metabolism in humans: a critical review.J. Lipid Res. 1989; 30: 785-807Google Scholar). This unfavorable alteration in lipid profile may be due to a reduction of LDL receptor (LDLR)-mediated clearance and/or the increased conversion of VLDL to LDL particles (9Nestel P.J. Effects of N-3 fatty acids on lipid metabolism.Annu. Rev. Nutr. 1990; 10: 149-167Google Scholar, 19Huff M.W. Telford D.E. Edmonds B.W. McDonald C.G. Evans A.J. Lipoprotein lipases, lipoprotein density gradient profile and LDL receptor activity in miniature pigs fed fish oil and corn oil.Biochim. Biophys. Acta. 1993; 1210: 113-122Google Scholar). Thus, plasma levels of LDL and apoB in subjects consuming FO could be affected both by VLDL apoB secretion and by LDL clearance rates. We have previously shown that apoB and TG secretion rates are independently regulated in human apoB transgenic (HuBTg) mouse strains (20Voyiaziakis E. Ko C. O'Rourke S.M. Huang L.S. Genetic control of hepatic apoB-100 secretion in human apoB transgenic mouse strains.J. Lipid Res. 1999; 40: 2004-2012Google Scholar). We have also shown that hepatic apoB-100 secretion rates are genetically determined in these strains (20Voyiaziakis E. Ko C. O'Rourke S.M. Huang L.S. Genetic control of hepatic apoB-100 secretion in human apoB transgenic mouse strains.J. Lipid Res. 1999; 40: 2004-2012Google Scholar, 21Ko C. Lee T.L. Lau P.W. Li J. Davis B.T. Voyiaziakis E. Allison D.B. Chua Jr., S.C. Huang L.S. Two novel quantitative trait loci on mouse chromosomes 6 and 4 independently and synergistically regulate plasma apoB levels.J. Lipid Res. 2001; 42: 844-855Google Scholar). In this report, we assess how genetic background affects plasma apoB and TG levels in response to FO feeding in various HuBTg mouse strains. We show that apoB and TG secretion rates are major determinants of the differential responses of plasma apoB and TG levels to FO feeding in two HuBTg mouse strains. Congenic HuBTg mice of the C57BL/6 (B6) background were generated as described previously (20Voyiaziakis E. Ko C. O'Rourke S.M. Huang L.S. Genetic control of hepatic apoB-100 secretion in human apoB transgenic mouse strains.J. Lipid Res. 1999; 40: 2004-2012Google Scholar). Male B6 congenic HuBTg mice were crossed with female mice of various inbred strains to generate F1 mouse strains as described previously (20Voyiaziakis E. Ko C. O'Rourke S.M. Huang L.S. Genetic control of hepatic apoB-100 secretion in human apoB transgenic mouse strains.J. Lipid Res. 1999; 40: 2004-2012Google Scholar). Inbred strains used were 129/Sv (129), BALB/c (BALB), C3H/HeJ (C3H), CBA/J (CBA), DBA/2J (DBA), and FVB/NJ (FVB). The F1 offspring 129 × B6, BABL × B6, C3H × B6, and FVB × B6 were described previously (20Voyiaziakis E. Ko C. O'Rourke S.M. Huang L.S. Genetic control of hepatic apoB-100 secretion in human apoB transgenic mouse strains.J. Lipid Res. 1999; 40: 2004-2012Google Scholar). In this report, the new F1 mouse strains CBA × B6 and DBA × B6 were generated. Inbred mouse strains used were purchased from the Jackson Laboratory (Bar Harbor, ME). The insertion site of the human apoB transgene has been reported previously (21Ko C. Lee T.L. Lau P.W. Li J. Davis B.T. Voyiaziakis E. Allison D.B. Chua Jr., S.C. Huang L.S. Two novel quantitative trait loci on mouse chromosomes 6 and 4 independently and synergistically regulate plasma apoB levels.J. Lipid Res. 2001; 42: 844-855Google Scholar), and presence of the human apoB transgene in each mouse was determined by PCR as described (22Callow M.J. Stoltzfus L.J. Lawn R.M. Rubin E.M. Expression of human apolipoprotein B and assembly of lipoprotein(a) in transgenic mice.Proc. Natl. Acad. Sci. USA. 1994; 91: 2130-2134Google Scholar). Mice were maintained in a 12 h light/dark cycle (light cycle: 7 AM–7 PM). Mice were fed either a chow diet, a FO diet, or a Western-type diet (WTD) and had free access to water. Rodent chow (PicoLab Rodent Chow, No. 5001; Purina Lab Chows, St. Louis, MO) consisted of 4.5% (wt/wt) fat, 0.02% (wt/wt) cholesterol, and was free of casein and sodium cholate. The FO diet (ICN Biomedical, No. 960195) consisted of 21% fat (20% menhaden oil and 1% corn oil). The major n-3 fatty acids in the menhaden oil were C20:5 (16.03%) and C22:6 (10.85%). α-Tocopherol (0.12%) was included as an antioxidant in the diet. To minimize the oxidation of n-3 fatty acids, the FO diet was stored under nitrogen atmosphere. The WTD diet (No.88137; Teklad Premier Laboratory Diets, Madison, WI) consisted of 21% (wt/wt) fat (polyunsaturated/saturated = 0.07), 0.15% (wt/wt) cholesterol, and 19.5% casein similarly free of sodium cholate. For fasting plasma samples and in vivo measurement of apoB and TG secretion experiments, mice were fasted for 4 h (10 AM–2 PM), retroorbitally bled, and/or subjected to experimental procedures immediately afterwards. For each experiment, age-matched male mice (12–20 weeks) were used unless otherwise indicated. A colorimetric enzyme assay was used to measure plasma total TG levels (No. 339-10, Sigma, St. Louis, MO). For plasma human apoB levels, an antibody specific to human apoB was used in immunoturbidimetric assays as described previously (20Voyiaziakis E. Ko C. O'Rourke S.M. Huang L.S. Genetic control of hepatic apoB-100 secretion in human apoB transgenic mouse strains.J. Lipid Res. 1999; 40: 2004-2012Google Scholar). Assessment of apoB and TG secretion rates in age-matched animals (n = 5–8/group) was performed as described previously (20Voyiaziakis E. Ko C. O'Rourke S.M. Huang L.S. Genetic control of hepatic apoB-100 secretion in human apoB transgenic mouse strains.J. Lipid Res. 1999; 40: 2004-2012Google Scholar). For the determination of apoB secretion rates, fasted mice were injected intravenously with a solution containing 200 μCi [35S]methionine and 500 mg/kg Triton WR1339 (Sigma) in 0.9% NaCl. Blood was taken at 0 min (just prior to injection), 30 min, and 60 min after the injection. Plasma samples (10 μl) were subjected to 4% SDS-PAGE followed by fluorography. Both B-100 and B-48 bands were cut from dried gels and counted in a liquid scintillation counter. Both B-100 and B-48 protein counts were normalized by TCA-precipitable counts in the given plasma sample and expressed as protein count per 10 μl of plasma (cpm/10 μl), as previously described (20Voyiaziakis E. Ko C. O'Rourke S.M. Huang L.S. Genetic control of hepatic apoB-100 secretion in human apoB transgenic mouse strains.J. Lipid Res. 1999; 40: 2004-2012Google Scholar). ApoB secretion rates (cpm/10 μl plasma/0.5 h) were calculated by subtracting normalized protein counts at the 30 min time point from normalized protein counts at the 60 min time point. The Triton WR1339 method described above was also employed to determine TG secretion rates with the exclusion of [35S]methionine. Mice were bled at 0 min (before injection), 60 min, and 120 min after injection. Plasma samples from the 0 min, 60 min, and 120 min time points were measured for TG levels. The TG secretion rate was calculated by subtracting the TG level at the 60 min time point from the TG level at the 120 min time point and expressed as mg/dl/h. Total cellular RNA was isolated from the livers using the guanidinium thiocyanate method (23Chomczynski P. Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.Anal. Biochem. 1987; 162: 156-159Google Scholar). The probes used for mouse LDLR (24Jiang X.C. Masucci-Magoulas L. Mar J. Lin M. Walsh A. Breslow J.L. Tall A. Down-regulation of mRNA for the low density lipoprotein receptor in transgenic mice containing the gene for human cholesteryl ester transfer protein. Mechanism to explain accumulation of lipoprotein B particles.J. Biol. Chem. 1993; 268: 27406-27412Google Scholar) and microsomal TG transfer protein (MTP) (25Siri P. Candela N. Zhang Y.L. Ko C. Eusufzai S. Ginsberg H.N. Huang L.S. Post-transcriptional stimulation of the assembly and secretion of triglyceride-rich apolipoprotein B lipoproteins in a mouse with selective deficiency of brown adipose tissue, obesity, and insulin resistance.J. Biol. Chem. 2001; 276: 46064-46072Google Scholar) were described previously. The RNA probe for human apoB was derived from a cDNA clone, pB352, containing exon 26 sequences (640 bp) of the human apoB gene. A fragment of 274 bp was isolated for probe synthesis by digesting the pB352 clone with ScaI and NcoI enzymes. RNA probes for mouse apoB (26Ludwig E.H. Levy-Wilson B. Knott T. Blackhart B.D. McCarthy B.J. Comparative analysis of sequences at the 5′ end of the human and mouse apolipoprotein B genes.DNA Cell Biol. 1991; 10: 329-338Google Scholar), acyl-CoA oxidase (AOX) (27Nohammer C. El-Shabrawi Y. Schauer S. Hiden M. Berger J. Forss-Petter S. Winter E. Eferl R. Zechner R. Hoefler G. cDNA cloning and analysis of tissue-specific expression of mouse peroxisomal straight-chain acyl-CoA oxidase.Eur. J. Biochem. 2000; 267: 1254-1260Google Scholar), carnitine palmitoyltransferase I (CPTI) (GenBank Accession number AF017175) (28Cox K.B. Johnson K.R. Wood P.A. Chromosomal locations of the mouse fatty acid oxidation genes Cpt1a, Cpt1b, Cpt2, Acadvl, and metabolically related Crat gene.Mamm. Genome. 1998; 9: 608-610Google Scholar), fatty acid synthase (FAS) (29Paulauskis J.D. Sul H.S. Structure of mouse fatty acid synthase mRNA. Identification of the two NADPH binding sites.Biochem. Biophys. Res. Commun. 1989; 158: 690-695Google Scholar), sterol responsive element binding protein 1c (SREBP1c) (30Shimomura I. Shimano H. Horton J.D. Goldstein J.L. Brown M.S. Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells.J. Clin. Invest. 1997; 99: 838-845Google Scholar), and peroxisome proliferator-activated receptor α (PPARα) (GenBank Accession number NM_011144) (31Gearing K.L. Crickmore A. Gustafsson J.A. Structure of the mouse peroxisome proliferator activated receptor alpha gene.Biochem. Biophys. Res. Commun. 1994; 199: 255-263Google Scholar) were generated by amplification of the target gene from liver RNA (male B6 mice) by RT-PCR. PCR primers used and the size of amplified products for each probe are shown in Table 1. PCR products were cloned into a PCRII vector using a TA cloning kit obtained from Invitrogen (Carlsbad, CA). DNA sequences of each clone were verified by DNA sequencing using an ABI 377 automatic DNA sequencer (Perkin Elmer).TABLE 1PCR primer sequences for mouse RNA probesGenePrimerPrimer Sequence (5′ → 3′)PCR Size (bp)ApoBSenseAGT GCC TGC AGT GGA TCA AGT ACC TGC223AntisenseTGG ACA GCT GAA GCT TAA GTT TTC CAG GACAOXSenseTCA ACA GCC CAA CTG TGA CTT CCA TTA227AntisenseTCA GGT AGC CAT TAT CCA TCT CTT CACPTISenseCCA GGC TAC AGT GGG ACA TT209AntisenseGAA CTT GCC CAT GTC CTT GTFASSenseTCA CCA CTG TGG GCT CTG CAG AGA AGC GAG330AntisenseTGT CAT TGG CCT CCT CAA AAA GGG CGT CCAPPARαSenseGTG GCT GCT ATA ATT TGC TGT G131AntisenseGAA GGT GTC ATC TGG ATG GTTSREPB1cSenseATC GGC GCG GAA GCT GTC GGG GTA GCG TC116AntisenseACT GTC TTG GTT GTT GAT GAG CTG GAG CATAOX, acyl-CoA oxidase; apoB, apolipoprotein B; CPTI, carnitine palmitoyltransferase; FAS, fatty acid synthase; PPARα, peroxisome proliferator-activated receptor α; SREBP1c, sterol responsive element binding protein 1c. Open table in a new tab AOX, acyl-CoA oxidase; apoB, apolipoprotein B; CPTI, carnitine palmitoyltransferase; FAS, fatty acid synthase; PPARα, peroxisome proliferator-activated receptor α; SREBP1c, sterol responsive element binding protein 1c. Antisense probes were synthesized using an in vitro transcription kit obtained from Promega (Madison, WI) and 32P-αCTP (800 Ci/mmol). Mouse β-actin (a 100 bp Hinf I fragment), cyclophilin, or GADPH (Ambion Co., Austin, TX) were used as reference RNA to normalize for variation in RNA loading in RNase protection assays. RNase protection assays were carried out as described previously (25Siri P. Candela N. Zhang Y.L. Ko C. Eusufzai S. Ginsberg H.N. Huang L.S. Post-transcriptional stimulation of the assembly and secretion of triglyceride-rich apolipoprotein B lipoproteins in a mouse with selective deficiency of brown adipose tissue, obesity, and insulin resistance.J. Biol. Chem. 2001; 276: 46064-46072Google Scholar). Briefly, total cellular RNA (10 μg) was hybridized to a test riboprobe and a reference riboprobe in a hybridization buffer (30 μl) and incubated at 48°C overnight. For apoB probes, hybridization was carried out at 65°C to allow species-specific reactions with either a human or a mouse apoB probe. Following overnight hybridization, 20 units of RNase T2 (Life Technologies, Rockville, MD) was added to the mix. After incubation at 37°C for 2 h, RNase was removed by phenol extraction and protected RNA fragments were ethanol-precipitated, resuspended in 5 μl of loading buffer (95% formamide, 0.05% xylene cyanol, 0.05% bromphenol blue, 20 mM EDTA), and separated in 5% or 8% PAGE/7 M urea gels. Dried gels were exposed to X-ray film for 1 or 2 days at −80°C. For quantification, protected RNA fragments were cut and radioactivity was counted in a liquid scintillation counter. To determine genetic effects on the response to FO feeding, age-matched mice of the B6 and six F1 HuBTg strains were fed a low-fat chow diet and then switched to a high-fat diet enriched in FO for 2 weeks. Plasma samples were collected from animals before and 2 weeks after starting FO feeding, and fasting plasma human apoB levels were then measured. As shown in Table 2, plasma apoB levels in chow-fed male animals varied among the seven mouse strains. The effects of the genetic background on plasma apoB levels in some of these F1 HuBTg mouse strains have been described previously (20Voyiaziakis E. Ko C. O'Rourke S.M. Huang L.S. Genetic control of hepatic apoB-100 secretion in human apoB transgenic mouse strains.J. Lipid Res. 1999; 40: 2004-2012Google Scholar). Table 2 also shows that the response of plasma apoB levels to FO feeding varied among the seven mouse strains tested. Plasma apoB levels were slightly increased (10%), but not significantly, in the parental B6 HuBTg strain after 2 weeks of FO feeding. However, plasma apoB levels in all six F1 mouse strains tested were significantly increased by FO. Increases ranged from 25% in the BALB × B6 strain to 60% in the 129 × B6 strain (Table 2). Plasma apoB levels were increased by FO by ∼40% (38–46%) in the other four mouse strains (i.e., C3H × B6, CBA × B6, DBA × B6, and FVB × B6). Unlike levels in male B6 HuBTg mice, plasma apoB levels in female B6 HuBTg mice were increased significantly by FO (data not shown). The response to FO in female B6 HuBTg mice was similar to that in female mice of the F1 HuBTg strains. Therefore, only data derived from male mice are shown in this report.TABLE 2ApoB responsiveness to fish oil feedingHuBTgaAge-matched male HuBTg mice were fed a chow diet and then switched to a FO diet or a WTD for 2 weeks. Blood samples were collected before and 2 weeks after high-fat-diet feeding.StrainNApoBbFasting plasma samples were measured for human apoB and presented as means ± SD mg/dl.FO/ChowRatiogRatio of plasma apoB levels in FO-fed versus chow-fed or FO-fed versus WTD-fed animals reflects percent differences in the two groups of animals.P ValuehPlasma apoB levels between any two diet groups within each strain were compared using Student's t-test.C versus FOFO/WTDRatiogRatio of plasma apoB levels in FO-fed versus chow-fed or FO-fed versus WTD-fed animals reflects percent differences in the two groups of animals.P ValuehPlasma apoB levels between any two diet groups within each strain were compared using Student's t-test.FO versus WTDChowcComparisons were made between B6 and any given F1 HuBTg strain using Student's t-test.FOWTDmg/dl%%B61078 ± 1586 ± 11103 ± 141100.283 0.02129 × B6553 ± 5fP < 0.0001.85 ± 6106 ± 12160<0.00180 0.008BALB × B6564 ± 4dP < 0.05.80 ± 999 ± 111250.00781 0.02C3H × B6557 ± 5eP < 0.01.83 ± 781 ± 7146<0.001102 0.6CBA × B6364 ± 1dP < 0.05.88 ± 4105 ± 6138<0.00184 0.02DBA × B6379 ± 7113 ± 9152 ± 101430.00674 0.007FVB × B6585 ± 16122 ± 9122 ± 261440.001100 1BALB, BALB/c; B6, C56BL/6; CBA, CBA/J; C3H, C3H/HeJ; DBA, DBA/2J; FVB, FVB/NJ; FO, fish oil HuBTg, human apoB transgenic mouse; WTD, Western-type diet; 129, 129/Sv.a Age-matched male HuBTg mice were fed a chow diet and then switched to a FO diet or a WTD for 2 weeks. Blood samples were collected before and 2 weeks after high-fat-diet feeding.b Fasting plasma samples were measured for human apoB and presented as means ± SD mg/dl.c Comparisons were made between B6 and any given F1 HuBTg strain using Student's t-test.d P < 0.05.e P < 0.01.f P < 0.0001.g Ratio of plasma apoB levels in FO-fed versus chow-fed or FO-fed versus WTD-fed animals reflects percent differences in the two groups of animals.h Plasma apoB levels between any two diet groups within each strain were compared using Student's t-test. Open table in a new tab BALB, BALB/c; B6, C56BL/6; CBA, CBA/J; C3H, C3H/HeJ; DBA, DBA/2J; FVB, FVB/NJ; FO, fish oil HuBTg, human apoB transgenic mouse; WTD, Western-type diet; 129, 129/Sv. The increases in plasma apoB levels by a FO-enriched diet in these mouse strains were likely due to the relatively high fat content (21%) compared with the chow diet, which has a low fat content (4.5%). In a separate set of experiments, male HuBTg mice were fed a WTD (21% fats, mainly saturated) for 2 weeks. As shown in Table 2, plasma apoB levels were lower in FO-fed B6 HuBTg mice compared with WTD-fed B6 HuBTg mice (17% reduction, P = 0.02). Similar results (16–26% reduction) were observed in 129 × B6, BALB × B6, CBA × B6, and DBA × B6 F1 strains (Table 2). However, in C3H × B6 and FVB × B6 HuBTg mouse strains, plasma apoB levels were not lower in FO-fed animals compared with WTD-fed animals. Taken together, these data showed that genetic background affects the response of plasma apoB levels to FO feeding in HuBTg mouse strains. We intended to determine the genetic basis of strain differences in the response of apoB to FO feeding. However, differences in basal plasma apoB levels complicate metabolic and genetic analyses on the strain differences in the response to FO. As shown in Table 2, four of the six F1 strains showed significant differences in basal plasma apoB levels compared with the parental B6 HuBTg strain. Therefore, we chose the FVB × B6, one of the two strains with similar basal plasma apoB levels compared with the parental B6 HuBTg strain, for further studies to assess possible mechanisms underlying strain differences in the response to FO. We note that FO feeding significantly increased plasma apoB levels in the FVB × B6 HuBTg strain (43% increase), but had a minimal effect on plasma apoB levels in the parental B6 HuBTg strain. On the other hand, saturated fat-enriched WTD increased plasma apoB levels in both B6 and FVB × B6 HuBTg strains by 32% and 43%, respectively. Interestingly, the mean body weight was not changed before and after FO feeding in the B6 HuBTg mice (29 ± 4 vs. 28 ± 3 g), whereas the body weight was significantly increased after FO feeding in FVB × B6 HuBTg mice (before vs. after = 38 ± 2 vs. 41 ± 1 g, P = 0.006). Similarly, the mean body weight was not changed before and after WTD feeding in B6 HuBTg mice (26 ± 2 vs. 27 ± 2 g), whereas the body weight was significantly increased after WTD feeding in FVB × B6 HuBTg mice (32 ± 2 vs. 37 ± 3 g, P = 0.047). To determine whether the strain differences in the responsiveness of plasma apoB levels to FO are regulated by apoB secretion rates, clearance rates, or both, chow-fed and FO-fed mice (n = 6/group) were assessed for in vivo apoB secretion rates. Age-matched male HuBTg mice were injected with Triton WR1339 and [35S]methionine as described in Materials and Methods. Plasma samples were collected at 30 min and 60 min time points followed by SDS-PAGE. Results are shown in Fig. 1. These results showed that the hepatic apoB-100 secretion rate in FO-fed B6 HuBTg mice did not statistically differ from those in chow-fed B6 HuBTg mice (Fig. 1A, left panels of 1C, 1D). Hepatic apoB-48 secretion rates were not significantly different between FO-fed and chow-fed B6 HuBTg mice either (Fig. 1A, left panels of 1C. 1D). In contrast, hepatic apoB-100 secretion was increased by 58% (P = 0.003) in the FO-fed FVB × B6 mice compared with chow-fed animals (Fig. 1B, right panels of 1C, 1D). Hepatic apoB-48 secretion rates were also increased by 49% (P = 0.005) in FO-fed FVB × B6 HuBTg mice compared with chow-fed animals (Fig. 1B, right panels of 1C, 1D). Overall, these results showed that FO feeding had a minimal effect on hepatic apoB secretion rates and on plasma apoB levels in B6 HuBTg mice. On the other hand, FO feeding markedly increased apoB secretion rates in FVB × B6 HuBTg mice. The increase of apoB secretion rates could account for the increase of plasma apoB levels observed in these animals. Thus, these data showed that differential hepatic apoB secretion rates were a major contributor to the strain differences in the response of plasma apoB to FO feeding in the B6 and the FVB × B6 HuBTg strains. To assess the contribution of LDL clearance rates to plasma apoB levels, we measured hepatic LDLR mRNA levels in both chow-fed and FO-fed animals. Total liver cellular RNA samples isolated from both FO-fed male B6 and FVB × B6 mice and their chow-fed controls (n = 5–6/diet/strain) were subjected to RNase protection assays. Representative samples are shown in Fig. 2. These results revealed an ∼30% decrease in LDLR mRNA levels in FO-fed B6 HuBTg mice compared with chow-fed B6 HuBTg mice (FO vs. chow = 670 ± 85 vs. 916 ± 88 cpm, P < 0.001). These data indicate a likely decrease in LDL clearance in these animals and may explain the slight incr" @default.
• W2120634442 created "2016-06-24" @default.
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• W2120634442 date "2003-10-01" @default.
• W2120634442 modified "2023-10-17" @default.
• W2120634442 title "A fish oil diet produces different degrees of suppression of apoB and triglyceride secretion in human apoB transgenic mouse strains" @default.
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• W2120634442 doi "https://doi.org/10.1194/jlr.m300172-jlr200" @default.
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