Dietary conjugated linoleic acid lowers plasma cholesterol during cholesterol supplementation, but accentuates the atherogenic lipid profile during the acute phase response in hamsters.

Conjugated linoleic acid (CLA) reportedly exerts anticarcinogenic and antiatherosclerotic effects in animals. To test the hypothesis that the putative antiatherosclerotic effect of CLA might derive from an anti-inflammatory or antioxidant action on lipoprotein metabolism, an acute phase response (APR) was elicited in hamsters while varying dietary cholesterol and vitamin E intakes in two experiments. The effect of CLA intake (to 1%) was examined with 0% (Experiment 1, 7 wk) and 0 or 0.3% (Experiment 2, 12 wk) cholesterol, at which point APR was induced. In hamsters not fed dietary cholesterol (Experiment 1), CLA exaggerated the rise in plasma and LDL cholesterol observed during the APR. When CLA was fed concurrently with cholesterol (Experiment 2), plasma and liver cholesterol were reduced up to 40% independent of the APR. In addition, CLA decreased body weight gain and adipose reserves in Experiment 1, but not in Experiment 2. Because CLA failed to attenuate APR and was not influenced by vitamin E status, an antioxidant/anti-inflammatory role was not apparent. However, the reduced burden on liver and lipoprotein cholesterol induced by CLA during cholesterol feeding, suggests that CLA curtailed cholesterol absorption, whereas the rise during APR suggests that CLA exaggerated the impaired clearance of plasma cholesterol associated with acute inflammation.

Hematopoiesis and retinoids: development and disease.

Retinoids function as activating ligands for a class of nuclear receptors that control gene expression programs for a wide range of tissues and organs during embryogenesis and throughout life. Over the years, three sets of observations have spurred interest in the function of retinoids with respect to development and disease of hematopoietic cells. Since the 1920s, epidemiological studies indicated altered hematopoiesis in vitamin A-deficient (VAD) human populations. More recently, the ability of retinoids to affect various aspects of hematopoietic development has been demonstrated in vitro. Finally, it was discovered that the gene encoding a retinoid receptor is a key target for chromosomal translocations that cause acute promyelocytic leukemia (APL). More recent investigations using targeted gene disruptions, VAD animal models, and mouse models of leukemia have continued to shed light on the function of the retinoid pathway in blood cells. It is now clear that retinoids are required for normal hematopoiesis during both yolk sac and fetal liver stages of hematopoiesis, while the pathway has at least modulatory functions for bone marrow derived progenitors. Studies of normal development and APL have provided complementary insight into the molecular control of blood cell differentiation. Here we review the evidence for retinoid requirements in hematopoiesis and also summarize current ideas regarding how this pathway is subverted in leukemia.

Retinoid signaling regulates primitive (yolk sac) hematopoiesis.

It is known from nutritional studies that vitamin A is an important factor for normal hematopoiesis, though it has been difficult to define its precise role. The vitamin A-deficient (VAD) quail embryo provides an effective ligand "knockout" model for investigating the function of retinoids during development. The VAD embryo develops with a significant reduction in erythroid cells, which has not been noted previously. Activation of the primitive erythroid program and early expression of the erythroid marker GATA-1 occurs, though GATA-1 levels eventually decline, consistent with the erythropoietic and hemoglobin deficits. However, from its early stages, the GATA-2 gene fails to be expressed normally in VAD embryos. The bone morphogenetic protein (BMP)-signaling pathway regulates GATA-2, and BMP4 expression becomes reduced in the caudal embryonic region of VAD embryos. Adding BMP4 to cultured VAD-derived explants rescues the production of erythroid cells, whereas normal embryos cultured in the presence of the BMP antagonist noggin are defective in primitive hematopoiesis. We find that cell clusters of primitive blood islands undergo an inappropriate program of apoptosis in the VAD embryo, which can explain the deficit in differentiated primitive blood cells. We propose that vitamin A-derived retinoids are required for normal yolk sac hematopoiesis and that an embryonic retinoid-BMP-GATA-2 signaling pathway controls progenitor cell survival relevant to primitive hematopoiesis.