Glucose Regulates the Expression of the Apolipoprotein A5 Gene

Abstract

Abbreviations: APOA5, the human apolipoprotein A5 gene; apoa5, the rodent apolipoprotein A5 gene; apoA-V, the human protein; PI3K, the phosphatidylinositol 3-kinase; PP1/PP2A, the protein phosphatases 1/2A; USF, the upstream stimulatory factor; SREBP-1c, the sterol response element binding protein-1c 2 ABSTRACTThe apolipoprotein A5 gene (APOA5) is a key player in determining triglyceride concentrations in humans and mice. Since diabetes is often associated with hypertriglyceridemia, this study explores whether APOA5 gene expression is regulated by alteration in glucose homeostasis and the related pathways. D-glucose activates APOA5 gene expression in a time-and dose-dependent manner in hepatocytes, and the glycolytic pathway involved was determined using D-glucose analogs and metabolites. Together, transient transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation assays show that this regulation occurs at the transcriptional level through an increase of USF1/2 binding to an E-box in the APOA5 promoter. We show that this phenomenon is not due to an increase of mRNA or protein expression levels of USF. Using protein phosphatases 1 and 2A inhibitor, we demonstrate that D-glucose regulates APOA5 gene via a dephosphorylation mechanism, thereby resulting in an enhanced USF1/2-promoter binding. Last, subsequent suppressions of USF1/2 and phosphatases mRNA through siRNA gene silencing abolished the regulation. We demonstrate that APOA5 gene is up regulated by D-glucose and USF through phosphatase activation. These findings may provide a new cross talk between glucose and lipid metabolism.3

Gene-Gene Interaction between <i>APOA5</i> and <i>USF1</i>: Two Candidate Genes for the Metabolic Syndrome

“…Further examples of regulators of APOA5 are RORa, PPARa, and LXR [8]. Recently, Nowak et al [22] could demonstrate the Table 4. × SNP 2 (all continuous), SNP coding: 0 = homozygous for major allele, 1 = heterozygous, 2 = homozygous for minor allele.…”

Metabolic interplay between white, beige, brown adipocytes and the liver

“…Several polymorphisms in the apoA5 gene are important determinants of LPL activity and plasma TG levels in the general population [34]. Furthermore, apoA5 expression is regulated by insulin and glucose [38], and apoA5 deficient mice exhibit increased insulin sensitivity [39], indicating that apoA5 plays a role in the regulation of systemic metabolism. In contrast to apoA5 and apoC2, the liver-derived apolipoproteins C1 and C3 (apoC1, apoC3) are inhibitors of LPL and thus inhibit fatty acid uptake in adipose tissues and other organs [7].…”

APOA1/A5Variants and Haplotypes as a Risk Factor for Obesity and Better Lipid Profiles in a Brazilian Elderly Cohort

“…It has recently been shown that D-glucose regulates APOA5 expression by dephosphorylation [36], suggesting an involvement of APOA5 in glucose metabolism [17]. Another previous study including four regions of Europe also showed that this variant influenced insulin and glucose levels after an oral glucose tolerance test (OGTT) [17].…”