Rickets and vitamin D deficiency in Alaska native children.

BACKGROUND: Rickets and vitamin D deficiency appeared to increase in Alaskan children starting in the 1990s. We evaluated the epidemiology of rickets and vitamin D deficiency in Alaska native (AN) children in 2001-2010. METHODS: We analyzed 2001-2010 visits with rickets or vitamin D deficiency diagnosis for AN and American Indian children and the general US population aged <10 years. We conducted a case-control study of AN rickets/vitamin D deficient cases and age- and region-matched controls. RESULTS: In AN children, annual rickets-associated hospitalization rate (2.23/100,000 children/year) was higher than the general US rate (1.23; 95% CI 1.08-1.39). Rickets incidence increased with latitude. Rickets/vitamin D deficiency cases were more likely to have malnutrition (OR 38.1; 95% CI 4.9-294), had similar breast-feeding prevalence, and were less likely to have received vitamin D supplementation (OR 0.23; 95% CI 0.1-0.87) than controls. CONCLUSIONS: Our findings highlight the importance of latitude, malnutrition, and lack of vitamin D supplementation as risk factors for rickets.

Peroxisome proliferator-activated receptor delta promotes very low-density lipoprotein-derived fatty acid catabolism in the macrophage.

Significant attention has focused on the role of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, recent advances have identified triglyceride-rich lipoproteins [e.g., very LDL (VLDL)] as independent risk predictors for this disease. We have previously demonstrated peroxisome proliferator-activated receptor (PPAR)delta, but not PPARgamma, is the major nuclear VLDL sensor in the macrophage, which is a crucial component of the atherosclerotic lesion. Here, we show that, in addition to beta-oxidation and energy dissipation, activation of PPARdelta by VLDL particles induces key genes involved in carnitine biosynthesis and lipid mobilization mediated by a recently identified TG lipase, transport secretion protein 2 (also named desnutrin, iPLA2zeta, and adipose triglyceride lipase), resulting in increased fatty acid catabolism. Unexpectedly, deletion of PPARdelta results in derepression of target gene expression, a phenotype similar to that of ligand activation, suggesting that unliganded PPARdelta suppresses fatty acid utilization through active repression, which is reversed upon ligand binding. This unique transcriptional mechanism assures a tight control of the homeostasis of VLDL-derived fatty acid and provides a therapeutic target for other lipid-related disorders, including dyslipidemia and diabetes, in addition to coronary artery disease.

PPAR gamma signaling exacerbates mammary gland tumor development.

Breast cancer cell lines that express the nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) can be prompted to undergo growth arrest and differentiation when treated with synthetic PPAR gamma ligands. To evaluate the therapeutic potential of increased PPAR gamma signaling in vivo, we generated transgenic mice that express a constitutively active form of PPAR gamma in mammary gland. These mice are indistinguishable from their wild-type littermates. However, when bred to a transgenic strain prone to mammary gland cancer, bigenic animals develop tumors with greatly accelerated kinetics. Surprisingly, in spite of their more malignant nature, bigenic tumors are more secretory and differentiated. The molecular basis of this tumor-promoting effect may be an increase in Wnt signaling, as ligand activation of PPAR gamma potentiates Wnt function in an in vivo model of this pathway. These results suggest that once an initiating event has taken place, increased PPAR gamma signaling serves as a tumor promoter in the mammary gland.

A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR.

The farnesoid X receptor (FXR) functions as a bile acid (BA) sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. However, BAs are poor reagents for characterizing FXR functions due to multiple receptor independent properties. Accordingly, using combinatorial chemistry we evolved a small molecule agonist termed fexaramine with 100-fold increased affinity relative to natural compounds. Gene-profiling experiments conducted in hepatocytes with FXR-specific fexaramine versus the primary BA chenodeoxycholic acid (CDCA) produced remarkably distinct genomic targets. Highly diffracting cocrystals (1.78 A) of fexaramine bound to the ligand binding domain of FXR revealed the agonist sequestered in a 726 A(3) hydrophobic cavity and suggest a mechanistic basis for the initial step in the BA signaling pathway. The discovery of fexaramine will allow us to unravel the FXR genetic network from the BA network and selectively manipulate components of the cholesterol pathway that may be useful in treating cholesterol-related human diseases.

Genetic profiling defines the xenobiotic gene network controlled by the nuclear receptor pregnane X receptor.

The orphan nuclear receptor pregnane X receptor (PXR) is essential for the transcriptional regulation of hepatic xenobiotic enzymes including the cytochrome 3A isoenzymes. These enzymes are central to the catabolism and clearance of most endogenous sterol metabolites (endobiotics) and a vast diversity of foreign compounds (xenobiotics) including pharmaceuticals, pesticides, and toxins encountered through diet and environmental exposure. To explore a broader role of PXR in the mammalian xenobiotic response, we have conducted a unique microarray gene profiling analysis on liver samples derived from PXR knockout mice and mice expressing a constitutively active variant, VP-hPXR. This genetically guided expression analysis enables targeting and restriction of the PXR response to liver, and is devoid of side effects resulting from drugs and their metabolites. As with pharmacological studies, receptor-dependent genes include both phase I and phase II metabolic enzymes, as well as certain drug and anion transporters as principal PXR targets. Moreover, comparative analysis of data from both genetic and pharmacological arrays reveals a core network that represents a genetic description of the xenobiotic response.

PPARdelta is a very low-density lipoprotein sensor in macrophages.

Although triglyceride-rich particles, such as very low-density lipoprotein (VLDL), contribute significantly to human atherogenesis, the molecular basis for lipoprotein-driven pathogenicity is poorly understood. We demonstrate that in macrophages, VLDL functions as a transcriptional regulator via the activation of the nuclear receptor peroxisome proliferator-activated receptor delta. The signaling components of native VLDL are its triglycerides, whose activity is enhanced by lipoprotein lipase. Generation of peroxisome proliferator-activated receptor delta null macrophages verifies the absolute requirement of this transcription factor in mediating the VLDL response. Thus, our data reveal a pathway through which dietary triglycerides and VLDL can directly regulate gene expression in atherosclerotic lesions.

Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR).

The nuclear receptor PXR (pregnane X receptor) protects the body from hepatotoxicity of secondary bile acids such as lithocholic acid (LCA) by inducing expression of the hydroxylating cytochrome P450 enzyme CYP3A and promoting detoxification. We found that activation of PXR also increases the activity and gene expression of the phase II conjugating enzyme dehydroepiandrosterone sulfotransferase (STD) known to sulfate LCA to facilitate its elimination. This activation is direct and appears to extend to other xenobiotic sulfotransferases as well as to 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2), an enzyme that generates the donor cofactor for the reaction. Because sulfation plays an important role in the metabolism of many xenobiotics, prescription drugs, and toxins, we propose that PXR serves as a master regulator of the phase I and II responses to facilitate rapid and efficient detoxification and elimination of foreign chemicals.