Location: Diet, Genomics and Immunology LaboratoryTitle: Mechanisms responsible for hepatic very low density lipoprotein-apoB100 overproduction in Otsuka Long-Evans Tokushima fatty rats) Author
Submitted to: Atherosclerosis
Publication Type: Peer reviewed journal
Publication Acceptance Date: 3/29/2012
Publication Date: 4/11/2012
Citation: Qin, B., Anderson, R.A., Kuzuya, T., Kitaura, Y., Shinomura, Y. 2012. Mechanisms responsible for hepatic very low density lipoprotein-apoB100 overproduction in Otsuka Long-Evans Tokushima fatty rats. Atherosclerosis. 222:407-416. Interpretive Summary: Roughly 20 million Americans, and more than 150 million people world-wide, suffer from type 2 diabetes. Type 2 diabetes increases the chances of developing hypertension, heart disease, stroke, eye problems, kidney disease, amputations, and even Alzheimer’s disease. Animal models that closely mimic the disease are urgently needed. A relatively new model to study type 2 diabetes, the Long-Evans Tokushima Fatty rat model, has been proposed; however, the similarities to type 2 diabetes in humans regarding lipid metabolism and inflammation have not been evaluated. We sought to examine the mechanisms linking systemic/hepatic inflammation associated with insulin resistance and fat metabolism. Like humans with type 2 diabetes, the Otsuka Long-Evans Tokushima Fatty rats showed systemic inflammation, insulin resistance, and abnormal fat metabolism. These effects were very similar to those observed in humans. In conclusion, these abnormal gene and protein expressions of multiple pathways related to inflammation, insulin signaling and lipogenesis may be important underlying factors to study the causes of type 2 diabetes and associated diseases in humans. These data should be of benefit to scientists, medical personnel, and the lay public.
Technical Abstract: Overproduction of hepatic very low-density lipoprotein (VLDL)1 particles is a major abnormality of lipoprotein dysregulation in type 2 diabetes (T2D). We sought to examine the mechanisms linking systemic/hepatic inflammation associated with insulin resistance and apolipoprotein (apo) B100-containing VLDL1 production. At the age of 19 wks, Otsuka Long-Evans Tokushima Fatty (OLETF) rats showed systemic inflammation (plasma TNF-a 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 VLDL-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. The mRNA expressions of insulin receptor substrate 2, glucose transporters 1 and 2, and glycogen synthase were decreased, but phosphatase and tensin homolog deleted on chromosome ten and glycogen synthase kinase 3ß mRNAs and protein tyrosine phosphatase-1B protein 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. In conclusion, these abnormal gene and protein expressions of multiple pathways related to inflammatory, insulin signaling and lipogenesis may be important underlying factors in VLDL1-apoB100 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.