The metabolism of vitamin A and the diverse effects of its metabolites are tightly controlled by distinct retinoid-generating enzymes, retinoid-binding proteins and retinoid-activated nuclear receptors. Retinoic acid regulates differentiation and metabolism by activating the retinoic acid receptor and retinoid X receptor (RXR), indirectly influencing RXR heterodimeric partners. Retinoic acid is formed solely from retinaldehyde (Rald), which in turn is derived from vitamin A. Rald currently has no defined biologic role outside the eye. Here we show that Rald is present in rodent fat, binds retinol-binding proteins (CRBP1, RBP4), inhibits adipogenesis and suppresses peroxisome proliferator-activated receptor-c and RXR responses. In vivo, mice lacking the Rald-catabolizing enzyme retinaldehyde dehydrogenase 1 (Raldh1) resisted diet-induced obesity and insulin resistance and showed increased energy dissipation. In ob/ob mice, administrating Rald or a Raldh inhibitor reduced fat and increased insulin sensitivity. These results identify Rald as a distinct transcriptional regulator of the metabolic responses to a high-fat diet.Although vitamin A and its metabolite retinoic acid have therapeutic applications, frequent side effects limit their use 1-3 . In clinical trials involving β-carotene supplementation, worrisome increases in cardiovascular events and mortality have been noted, despite evidence suggesting possible beneficial vascular effects of this treatment 3 . These variable responses to retinoids probably derive from the fact that β-carotene and vitamin A (retinol) and their major metabolites-retinaldehyde (Rald) and retinoic acid-regulate diverse cellular responses, including development, immune function and vision 4,5 . The tight control of retinoid biology is evident in the elaborate system that governs the absorption, formation, transportation and action of these structurally and functionally distinct retinoid metabolites. Despite this, retinoids

Hyperglycemia can promote vascular complications by multiple mechanisms, with formation of advanced glycation endproducts (AGEs) and increased oxidative stress proposed to contribute to both macrovascular and microvascular complications. Many of the earliest pathologic responses to hyperglycemia are manifest in the vascular cells that directly encounter elevated blood glucose levels. In the macrovasculature, these include endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). In the microvasculature, these include ECs, pericytes (in retinopathy), and podocytes (in renal disease). Additionally, neovascularization arising from the vasa vasorum may promote atherosclerotic plaque progression and contribute to plaque rupture, thereby interconnecting macro- and microangiopathy.

Objectives-During inflammation, the serum amyloid A (SAA) content of HDL increases, whereas apolipoprotein A-I (apoA-I) and paraoxonase-1 (PON-1) decrease. It remains unclear whether SAA physically displaces apoA-I or if these changes derive from coordinated but inverse transcriptional regulation of the HDL apolipoprotein genes. Because cytokines stimulate the hepatic expression of inflammatory markers, we investigated their role in regulating SAA, apoA-I, and PON-1 expression. Methods and Results-A cytokine mixture (tumor necrosis factor [TNF]-␣, interleukin [IL]-1␤, and IL-6) simultaneously induced SAA and repressed apoA-I and PON-1 expression levels. These effects were partially inhibited in cells pretreated with either nuclear factor B (NF-B) inhibitors (pyrrolidine dithiocarbamate, SN50, and overexpression of super-repressor inhibitor B) or after exposure to the peroxisome proliferator-activated receptor-␣ (PPAR␣) ligands (WY-14643 and fenofibrate). Consistent with these findings, the basal level of SAA was increased, whereas apoA-I and PON-1 decreased in primary hepatocytes from PPAR␣-deficient mice as compared with wild-type mice. Moreover, neither WY-14643 nor fenofibrate had any effect on SAA, apoA-I, or PON-1 expression in the absence of PPAR␣. Conclusion-These