Apolipoprotein B mRNA editing and apolipoprotein gene expression in the liver of hyperinsulinemic fatty Zucker rats: Relationship to very low densitylipoprotein composition

We previously demonstrated increased apolipoprotein B (apoB) mRNA editing, elevated levels of mRNA for the catalytic component of the apoB mRNA editin g complex, apobec-1, and increased secretion of the product of the edited m RNA, apoB48, in very low density lipoproteins (VLDL) in primary cultures of Sprague-Dawley rat hepatocytes following insulin treatment. In order to de termine the effect of in vivo hy perinsulinemia on these processes, we dete rmined apoB mRNA editing, apobec-1 expression, hepatic expression of mRNA f or apoB and other VLDL apoproteins, and the quantity and composition of pla sma VLDL in the hyperinsulinemic fatty Zucker rat. Total apoB mRNA content of the livers of the fatty rats and lean littermates did not differ; howeve r, edited apoB message coding for hepatic apo B48, and abundance of mRNA fo r the catalytic subunit of the apoB mRNA editing complex, apobec-1, was inc reased by 1.7- and 3.3-fold, respectively, in fatty rats. ApoCIII mRNA abun dance was increased in livers of fatty rats as well, but the abundance of h epatic apoE mRNA in the fatty animal was not different from that of the lea n rat. Hepatic apoAI mRNA abundance was also increased in the fatty rats. A ssociated with increased apoB mRNA editing, was the 1.7-fold increase in th e fraction of apoB in plasma as apoB48 in fatty rats. VLDL-triglyceride and -apoB in plasma were 15- and 3-fold higher, respectively, in fatty Zucker rats compared to lean littermates, indicating both enrichment of VLDL with triglycerides and increased accumulation of VLDL particles, Increased hepat ic expression of mRNA for apoCIII and apoAI was associated with increased c ontent of apoC (and relative depletion of apoE) in VLDL of fatty rats, and plasma apoAI was increased in fatty Zucker rats, primarily in the HDL fract ion. The current study provides further evidence that chronic exposure to h igh levels of insulin influences both the quantity of and lipid/apoprotein composition of VLDL in plasma. The increased apoC and decreased apoE (as we ll as increased triglyceride) content of VLDL in the fatty Zucker rat obser ved in the current study may affect VLDL clearance and therefore may be a f actor in the observed accumulation of VLDL in the plasma of the fatty hyper insulinemic Zucker rats.