Abstract
We have examined the regulation of apolipoprotein A-I (apoA-I) gene expression in response to glucose and insulin. In Hep G2 cells, endogenous apoA-I mRNA was suppressed by one-half or induced 2-fold following 48 h of exposure to high concentrations of glucose (22.4 mM) or insulin (100 microunits/ml), respectively, compared with control. Transcriptional activity of the rat apoA-I promoter (-474 to -7) in Hep G2 cells paralleled endogenous mRNA expression, and this activity was dependent on the dose of glucose or insulin. Deletional analysis showed that a 50-base pair fragment spanning -425 to -376 of the promoter mediated the effects of both insulin and glucose. Within this DNA fragment there is a motif (-411 to -404) that is homologous to a previously identified insulin response core element (IRCE). Mutation of this motif abolished not only the induction of the promoter by insulin but also abrogated its suppression by glucose. Electrophoretic mobility shift assay analysis of nuclear extracts from Hep G2 cells revealed IRCE binding activity that formed a duplex with radiolabeled probe. The IRCE binding activity correlated with insulin induction of apoA-I expression. In summary, our data show that glucose decreases and insulin increases apoA-I promoter activity. This effect appears to be mediated by a single cis-acting element.
Highlights
The serum protein, apolipoprotein A-I,1 has intrinsic antiatherogenic properties and is the major apoprotein component of the high density lipoprotein particles [1, 2]
We have examined the regulation of apolipoprotein A-I (apoA-I) gene expression in response to glucose and insulin
Interest in this topic stems from the clinical observation showing that hyperglycemia arising from hypo-/hyperinsulinemic states such as diabetes mellitus decreases the levels of apoA-I [33]
Summary
The serum protein, apolipoprotein A-I (apoA-I), has intrinsic antiatherogenic properties and is the major apoprotein component of the high density lipoprotein particles [1, 2]. Increased abundance of apoA-I correlates inversely with the incidence of coronary arterial disease [3, 4] This beneficial feature of the protein arises from its pivotal role in a normal physiologic process called reverse cholesterol transport [5]. Previous epidemiologic studies have shown a clear inverse correlation between levels of apoA-I and the incidence of coronary artery disease in both normal and diabetic individuals [7, 8] This protective feature of apoA-I is of primary importance in the clinical setting of diabetes mellitus (DM) because these patients have a 2–3-fold higher risk of developing premature arterial atherosclerosis compared with the general population [8]. Regardless of whether the patient has insulin-dependent or non-insulindependent DM arising from hypo- or hyperinsulinemia, respectively, both diseases are associated with the enhanced risk of arteriosclerosis [10, 11]
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