Human acyl-CoA:cholesterol acyltransferase 2 gene expression in intestinal Caco-2 cells and in hepatocellular carcinoma

Abstract

Humans express two ACAT (acyl-CoA:cholesterol acyltransferase) genes, ACAT1 and ACAT2. ACAT1 is ubiquitously expressed, whereas ACAT2 is primarily expressed in intestinal mucosa and plays an important role in intestinal cholesterol absorption. To investigate the molecular mechanism(s) responsible for the tissue-specific expression of ACAT2, we identified five cis-elements within the human ACAT2 promoter, four for the intestinal-specific transcription factor CDX2 (caudal type homeobox transcription factor 2), and one for the transcription factor HNF1alpha (hepatocyte nuclear factor 1alpha). Results of luciferase reporter and electrophoretic mobility shift assays show that CDX2 and HNF1alpha exert a synergistic effect, enhancing the ACAT2 promoter activity through binding to these cis-elements. In undifferentiated Caco-2 cells, the ACAT2 expression is increased when exogenous CDX2 and/or HNF1alpha are expressed by co-transfection. In differentiated Caco-2 cells, the ACAT2 expression significantly decreases when the endogenous CDX2 or HNF1alpha expression is suppressed by using RNAi (RNA interference) technology. The expression levels of CDX2, HNF1alpha, and ACAT2 are all greatly increased when the Caco-2 cells differentiate to become intestinal-like cells. These results provide a molecular mechanism for the tissue-specific expression of ACAT2 in intestine. In normal adult human liver, CDX2 expression is not detectable and the ACAT2 expression is very low. In the hepatoma cell line HepG2 the CDX2 expression is elevated, accounting for its elevated ACAT2 expression. A high percentage (seven of fourteen) of liver samples from patients affected with hepatocellular carcinoma exhibited elevated ACAT2 expression. Thus, the elevated ACAT2 expression may serve as a new biomarker for certain form(s) of hepatocellular carcinoma.

TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation

“…Under normal conditions, based on mRNA, protein, and enzyme activity analyses, human ACAT1 is the major isoenzyme in almost all of the tissues or cells examined, and ACAT2 is most abundantly expressed in the epical epithelium of intestines (5)(6)(7)(8)(9). Relevant to our current study is the fact that ACAT1 is highly expressed in monocytes/macrophages forming the foam cells in atherosclerotic plaques, especially at the early stage of atherosclerosis development (8)(9)(10)(11).…”

TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2

“…Previous studies have shown that Hnf1 ␣ and caudal type homeobox transcription factor 2 function as activators of the human SOAT2 promoter in intestinal Caco2 cells ( 34 ). Ϫ / Ϫ mice.…”

Androgen‐mediated cholesterol metabolism in LNCaP and PC‐3 cell lines is regulated through two different isoforms of acyl‐coenzyme A: Cholesterol Acyltransferase (ACAT)

“…Regulation of these two genes is quite diverse in their localization and expression mechanisms [2]. ACAT1 expression is regulated by transcriptional factors such as STAT1a and Sp1 [23] while ACAT2 is regulated by Cdx2 and HNF1a [24]. STAT1a induction by interferon gamma has been shown to induce ACAT1 expression in human monocytes and thus this may be a possible activation pathway for this isoform [23].…”