Deletion of murine Arv1 results in a lean phenotype with increased energy expenditure.

BACKGROUND: ACAT-related enzyme 2 required for viability 1 (ARV1) is a putative lipid transporter of the endoplasmic reticulum that is conserved across eukaryotic species. The ARV1 protein contains a conserved N-terminal cytosolic zinc ribbon motif known as the ARV1 homology domain, followed by multiple transmembrane regions anchoring it in the ER. Deletion of ARV1 in yeast results in defective sterol trafficking, aberrant lipid synthesis, ER stress, membrane disorganization and hypersensitivity to fatty acids (FAs). We sought to investigate the role of Arv1 in mammalian lipid metabolism. METHODS: Homologous recombination was used to disrupt the Arv1 gene in mice. Animals were examined for alterations in lipid and lipoprotein levels, body weight, body composition, glucose tolerance and energy expenditure. RESULTS: Global loss of Arv1 significantly decreased total cholesterol and high-density lipoprotein cholesterol levels in the plasma. Arv1 knockout mice exhibited a dramatic lean phenotype, with major reductions in white adipose tissue (WAT) mass and body weight on a chow diet. This loss of WAT is accompanied by improved glucose tolerance, higher adiponectin levels, increased energy expenditure and greater rates of whole-body FA oxidation. CONCLUSIONS: This work identifies Arv1 as an important player in mammalian lipid metabolism and whole-body energy homeostasis.

Medical management of benign prostatic hyperplasia: a canine model comparing the in vivo efficacy of alpha-1 adrenergic antagonists in the prostate.

Medical management of benign prostatic hyperplasia (BPH) is an alternative to surgical treatment of this disease. A major target for pharmacologic therapy is the alpha-1 adrenergic receptor, since activation of this receptor by endogenous catecholamines is thought to contribute to outlet obstruction. In the present study, we compared the potency of various alpha-1 adrenergic antagonists against epinephrine-induced contraction of the canine prostate. The drugs tested were dibenzyline, prazosin, terazosin and YM617. The rank order of potency, comparing inhibitory constants (Ki's), was found to be YM617 >> prazosin > terazosin > dibenzyline. This study is the first to compare all of these drugs directly in the prostate in vivo. The rank order of potency of the drugs is similar to the rank order of potency at other alpha-1 receptors. These results demonstrate that 1) our model is useful in confirming activity of drugs at the alpha-1 receptor and 2) the prostate alpha-1 receptor is similar to other alpha-1 receptors. Whether activity at the alpha-1 adrenergic receptor is a sufficient determinant of clinical efficacy of these drugs remains to be determined.

Medical management of benign prostatic hyperplasia.

Medical management of clinical BPH is a reality. The only effective nonsurgical treatment now recommended is aimed at relieving the dynamic component of clinical BPH. Pharmacologic treatment using alpha-adrenoceptor antagonists may be used appropriately to manage patients with prostatism who are poor surgical risks but who could benefit from reduced sympathetic tone. In addition, alpha blockers are used to relieve acute retention, and to prevent retention when increased sympathetic discharge is expected. Thus far, nonsurgical therapy aimed at reducing the mechanical obstruction associated with BPH by prostatic size reduction has failed to produce consistent objective improvement. However, several drugs are now being investigated and may be effective for reducing prostatic size in patients with BPH. Clinical trials are complicated by a number of factors, especially very variable symptoms. Moreover, reduction in prostatic size induced by drugs is not permanent and regrowth occurs with drug withdrawal, necessitating chronic treatment. Ideally, future research should be aimed at the prevention of BPH at an early age. However, this presupposes a better understanding of the pathogenesis of BPH. BPH may not be a single, variable disease but a family of diseases with a number of predictable clinical courses. In the future, we should pay particular attention to histologic variability, to see if in fact different pathologic forms of BPH follow different clinical patterns. If urologists are to keep their predominant position in managing the patient with BPH, they will have to keep informed of medical treatment trials and of potential alternative treatment strategies to prostatectomy.