Abstract 109: Role of ApoAIV in ApoB Lipoprotein Assembly and Triglyceride Transport
Apolipoprotein A-IV (apoAIV) is a lipid binding protein expressed primarily in mammalian intestine and also in rodent liver. While in vitro studies have suggested a role of apoAIV in lipoprotein formation and triglyceride (TG) transport, limited evidence supports such a function in vivo. To explore if hepatic apoAIV is uniformly regulated by increased hepatic TG levels, as is the case in the intestine, we studied three distinct mouse models of hepatic steatosis. These included high fat diet (HFD)-fed wild type mice, mice overexpressing a constitutive active form of SREBP-1a (SREBP-1aTg), and mice in which hepatic TG hydrolysis is blunted (mice treated with an anti-sense oligonucleotide (ASO) targeting knockdown of CGI-58/ABHD5). High fat diet-fed mice displayed a 4.5-fold increase in liver TG content and a 10-fold increase in apoAIV mRNA expression and protein mass. SREBP-1aTg mouse liver demonstrated an ∼35-fold increase in hepatic TG, apoAIV mRNA and apoAIV protein. A linear correlation was observed between hepatic TG content and apoAIV mRNA expression in the HFD fed wild type and SREBP-1aTg mice (r2 = 0.6852; p < 0.01). Interestingly, while the TG content of CGI-58/ABHD5 knockdown animals increased by 4-fold, no corresponding increase in apoAIV expression was observed. To determine if the increase in apoAIV expression in the steatotic livers of SREPB-1aTg mice plays a role in the secretion of TG-rich apoB-containing lipoproteins, we crossed these mice with apoAIV knock out mice (A4-KO). The SREBP1a-Tg/A4-KO mice did not demonstrate a change in liver to body weight ratio or a change in hepatic TG content. Despite the large induction of apoAIV in the livers of SREBP1a-Tg mice, no difference was observed in hepatic TG production rates or VLDL particle size when apoAIV was deficient (SREBP1a-Tg/A4-KO). These results indicate that hepatic apoAIV expression is upregulated under conditions of enhanced lipogenesis, but is not altered under condition of defective TG hydrolysis. Furthermore, even under conditions of a 35-fold induction, apoAIV does not exert a detectable impact on TG transport or VLDL particle characteristics in mouse liver.
- © 2012 by American Heart Association, Inc.