title: Multiple factors and pathways involved in hepatic very low density lipoprotein-apoB100 overproduction in Otsuka Long-Evans Tokushima Fatty rats.
abstract: OBJECTIVE
  Overproduction of hepatic very low-density lipoprotein (VLDL) particles is a major abnormality of lipoprotein dysregulation in type 2 diabetes (T2D). We sought to examine the relationship between systemic/hepatic inflammation associated with insulin resistance and apolipoprotein (apo)B100-containing VLDL production.
  
  
  RESULTS
  At the age of 19 wks, Otsuka Long-Evans Tokushima Fatty (OLETF) rats showed systemic inflammation (plasma TNF-α and interleukin (IL)-6 levels increased), insulin resistance (plasma retinol binding protein 4 and soluble CD36 levels were higher), dyslipidemia and fatty liver (plasma and liver triglyceride and cholesterol levels were higher as well as total VLDL-, VLDL(1)-, VLDL(2)-apoB100 and VLDL-triglycerides were overproduced), compared with the control rats. In livers of OLETF rats, mRNA levels of tnf, il1b and il6 were increased, but an anti-inflammatory protein, zinc finger protein 36, and its mRNA expression were decreased. We also found that the liver mRNA, protein levels, and tyrosine phosphorylation (pY) of insulin receptor (InsR) substrate (IRS) 2, but not IRS1, were decreased in OLETF rats; pY of InsR and Akt protein and phospho-Akt (ser437) were also reduced; but protein tyrosine phosphatase-1B protein was overexpressed. The gene expressions of glucose transporters 1 and 2, and glycogen synthase were decreased, but phosphatase and tensin homolog deleted on chromosome ten and glycogen synthase kinase 3β mRNAs were overexpressed, compared with the controls. Sterol regulatory element binding protein-1c mRNA, ATP-binding cassette transporter A1 mRNA, microsomal triglyceride transfer protein mRNA/protein, and CD36 mRNA/protein levels were increased and lipoprotein lipase and Niemann-Pick c1-like1 mRNA levels were decreased, which are all involved in lipogenesis. Decreased sirtuins1-3 mRNA levels were also observed in OLETF rats.
  
  
  CONCLUSIONS
  These abnormal genes, proteins expression and phosphorylation of multiple pathways related to inflammatory, insulin signaling and lipogenesis may be important underlying factors in VLDL-apoB100 particles overproduction observed in T2D. Our data contribute to the further understanding of an association of dyslipoproteinemia with systemic metabolic disorders, fatty liver and dysregulated hepatic metabolic pathways.
authors.affiliation: United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics and Immunology Laboratory, Beltsville, MD 20705, USA. Bolin.Qin@ars.usda.gov
authors.forename: Bolin
authors.initials: B
authors.lastname: Qin
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
authors.forename: Teiji
authors.initials: T
authors.lastname: Kuzuya
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kitaura
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Shimomura
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005234:Fatty Liver / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D015398:Signal Transduction / Q000235:genetics; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
chemical_list: D053299:Apolipoprotein B-100; D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol; D037761:Sirtuins