Abnormal energy regulation may significantly contribute to the pathogenesis of obesity, diabetes mellitus, cardiovascular disease, and cancer. For rapid control of energy homeostasis, allosteric and posttranslational events activate or alter activity of key metabolic enzymes. For longer impact, transcriptional regulation is more effective, especially in response to nutrients such as long chain fatty acids (LCFA). Recent advances provide insights into how poorly water-soluble lipid nutrients [LCFA; retinoic acid (RA)] and their metabolites (long chain fatty acyl Coenzyme A, LCFA-CoA) reach nuclei, bind their cognate ligand-activated receptors, and regulate transcription for signaling lipid and glucose catabolism or storage: (i) while serum and cytoplasmic LCFA levels are in the 200 mircroM-mM range, real-time imaging recently revealed that LCFA and LCFA-CoA are also located within nuclei (nM range); (ii) sensitive fluorescence binding assays show that LCFA-activated nuclear receptors [peroxisome proliferator-activated receptor-alpha (PPARalpha) and hepatocyte nuclear factor 4alpha (HNF4alpha)] exhibit high affinity (low nM KdS) for LCFA (PPARalpha) and/or LCFA-CoA (PPARalpha, HNF4alpha)-in the same range as nuclear levels of these ligands; (iii) live and fixed cell immunolabeling and imaging revealed that some cytoplasmic lipid binding proteins [liver fatty acid binding protein (L-FABP), acyl CoA binding protein (ACBP), cellular retinoic acid binding protein-2 (CRABP-2)] enter nuclei, bind nuclear receptors (PPARalpha, HNF4alpha, CRABP-2), and activate transcription of genes in fatty acid and glucose metabolism; and (iv) studies with gene ablated mice provided physiological relevance of LCFA and LCFA-CoA binding proteins in nuclear signaling. This led to the hypothesis that cytoplasmic lipid binding proteins transfer and channel lipidic ligands into nuclei for initiating nuclear receptor transcriptional activity to provide new lipid nutrient signaling pathways that affect lipid and glucose catabolism and storage.

Growing axons use environmental cues to guide them to their targets. One class of cues is thought to be adhesion molecules on cells and in the extracellular matrix that axons interact with as they grow to their targets. In choosing between two possible pathways, the relative adhesiveness of the two substrates could be an important factor in controlling neurite growth. We conducted experiments in vitro to study how naturally occurring adhesion molecules influence neurite growth. Neurite growth rates, the degree of neurite fasciculation, the choices neurites make between two substrates, and the relative adhesiveness of different substrates were examined. We found that the relative adhesiveness of a substrate was a poor predictor of either axon growth rate or the degree of fasciculation. Furthermore, neurites showed little selectivity between three different naturally occurring substrates, L1, N-cadherin, and laminin. These results suggest that some adhesion molecules may serve as permissive substrates in that they can define axonal pathways but they do not provide information about which path to take at a choice point or about which direction to go along the path. Finally, these results suggest that substrates in vivo may not exert their effects on axon guidance principally via relative adhesiveness.

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Despite the importance of branched chain lipid oxidation in detoxification, almost nothing is known regarding factors regulating peroxisomal uptake, targeting, and metabolism. One peroxisomal protein, sterol carrier protein-x (SCP-x), is thought to catalyze a key thiolytic step in branched chain lipid oxidation. When mice with substantially lower hepatic levels of SCP-x were tested for susceptibility to dietary stress with phytol (a phytanic acid precursor and peroxisome proliferator), livers of phytol-fed female but not male mice i ) accumulated phytol metabolites (phytanic acid, pristanic acid, and ⌬ -2,3-pristanic acid); ii ) exhibited decreased fat tissue mass and increased liver mass/ body mass; iii ) displayed signs of histopathological lesions in the liver; and iv ) demonstrated significant alterations in hepatic lipid distributions. Moreover, both male and female mice exhibited phytol-induced peroxisomal proliferation, as demonstrated by liver morphology and upregulation of the peroxisomal protein catalase. In addition, levels of liver fatty acid binding protein, along with SCP-2 and SCP-x, increased, suggesting upregulation mediated by phytanic acid, a known ligand agonist of the peroxisomal proliferator-activated receptor ␣ . In summary, the present work establishes a role for SCP-x in branched chain lipid catabolism and demonstrates a sexual dimorphic response to phytol, a precursor of phytanic acid, in lipid parameters and hepatotoxicity.

Despite the importance of peroxisomal oxidation in branched-chain lipid (phytol, cholesterol) detoxification, little is known regarding the factors regulating the peroxisomal uptake, targeting, and metabolism of these lipids. Although in vitro data suggest that sterol carrier protein (SCP)-x plays an important role in branched-chain lipid oxidation, the full physiological significance of this peroxisomal enzyme is not completely clear. To begin to resolve this issue, SCP-x-null mice were generated by gene ablation of SCP-x from the SCP-x/SCP-2 gene and fed a phytol-enriched diet to characterize the effects of lipid overload in a system with minimal 2/3-oxoacyl-CoA thiolytic activity. It was shown that SCP-x gene ablation 1) did not result in reduced expression of SCP-2 (previously thought to be derived in considerable part by posttranslational cleavage of SCP-x); 2) increased expression levels of key enzymes involved in alpha- and beta-oxidation; and 3) altered lipid distributions, leading to decreased hepatic fatty acid and triglyceride levels. In response to dietary phytol, lack of SCP-x resulted in 1) accumulation of phytol metabolites despite substantial upregulation of hepatic peroxisomal and mitochondrial enzymes; 2) reduced body weight gain and fat tissue mass; and 3) hepatic enlargement, increased mottling, and necrosis. In summary, the present work with SCP-x gene-ablated mice demonstrates, for the first time, a direct physiological relationship between lack of SCP-x and decreased ability to metabolize branched-chain lipids.