The apoA-I/C-III/A-IV gene cluster, like most intestinespecific genes, displays a specific pattern of expression along the intestinal cephalocaudal and crypt-to-villus axes. We have shown that this specific pattern of expression requires the distal apoA-IV promoter and the apoC-III enhancer. Using a new set of transgenic mice, we demonstrate here that the restriction of apoA-IV gene transcription to villus enterocytes requires a hormoneresponsive element (HRE) located within the apoA-IV distal promoter. We showed, using nuclear extracts from villus or crypt epithelial cells, that this HRE bound the transcription factor hepatic nuclear factor 4 (HNF-4). We also found that the HNF-4␥ isoform was produced only in the villus, whereas the HNF-4␣ isoform was produced along the entire length of the crypt-to-villus axis. Our results demonstrate that the HRE of the distal apoA-IV promoter is responsible for the restriction of gene expression to villus epithelial cells and that this HRE binds HNF-4 isoforms. The in vivo observation of parallel gradients for apoA-IV and HNF-4␥ gene expression raises questions concerning whether this transcription factor plays a specific role in the control of enterocyte differentiation.

Spatial gene expression in the intestine is mediated by specific regulatory sequences. The three genes of the apoA-I/C-III/A-IV cluster are expressed in the intestine following cephalocaudal and crypt-to-villus axes. Previous studies have shown that the -780/-520 enhancer region of the apoC-III gene directs the expression of the apoA-I gene in both small intestinal villi and crypts, implying that other unidentified elements are necessary for a normal intestinal pattern of apoA-I gene expression. In this study, we have characterized transgenic mice expressing the chloramphenicol acetyltransferase gene under the control of different regions of the apoC-III and apoA-IV promoters. We found that the -890/؉24 apoC-III promoter directed the expression of the reporter gene in crypts and villi and did not follow a cephalocaudal gradient of expression. In contrast, the ؊700/؉10 apoA-IV promoter linked to the ؊500/؊890 apoC-III enhancer directed the expression of the reporter gene in enterocytes with a pattern of expression similar to that of the endogenous apoA-IV gene. Furthermore, linkage of the ؊700/؊310 apoA-IV distal promoter region to the ؊890/؉24 apoC-III promoter was sufficient to restore the appropriate pattern of intestinal expression of the reporter gene. These findings demonstrate that the ؊700/؊310 distal region of the apoA-IV promoter contains regulatory elements that, in combination with proximal promoter elements and the ؊500/ ؊890 enhancer, are necessary and sufficient to restrict apoC-III and apoA-IV gene expression to villus enterocytes of the small intestine along the cephalocaudal axis.

Thrombotic microangiopathy (TMA) can occur during the course of human immunodeficiency virus (HIV) infection. Clinical and pathological data for 29 patients with TMA and HIV infection were recorded. In a retrospective case-control study, we analyzed the link between opportunistic infections or drug therapies and TMA. Twenty-five patients (mean CD4+ cell count +/- SD, 71.9 +/- 18.3/mm3) had renal impairment, and four had neurological dysfunction. In one-half the cases, the disease was progressive with isolated fragmentation anemia appearing several months before the clinical symptoms. The diagnosis of TMA was confirmed by histological examination of kidney biopsy specimens (18 cases). Endothelial cytomegalovirus (CMV) inclusions were associated with TMA in nine of 18 cases, whereas histological examination did not detect CMV in any control specimens (P < .001). The case-control study demonstrated a link between TMA and clinical CMV infection (odds ratio, 3.9; 95% confidence interval, 1.1-14). We conclude that TMA is a late complication of HIV infection and can be associated with systemic CMV infection in this setting.