SUMMARY Ultraviolet light is an established carcinogen yet evidence suggests that UV-seeking behavior has addictive features. Following UV exposure, epidermal keratinocytes synthesize Proopiomelanocortin that is processed to Melanocyte Stimulating Hormone, inducing tanning. We show that in rodents another POMC-derived peptide, β-endorphin, is coordinately synthesized in skin, elevating plasma levels after low-dose UV. Increases in pain-related thresholds are observed, and reversed by pharmacologic opioid antagonism. Opioid blockade also elicits withdrawal signs after chronic UV exposure. This effect was sufficient to guide operant behavioral choices to avoidance of opioid withdrawal (conditioned place aversion). These UV-induced nociceptive and behavioral effects were absent in β-endorphin knockout mice and in mice lacking p53-mediated POMC induction in epidermal keratinocytes. While primordial UV addiction, mediated by the hedonic action of β-endorphin and anhedonic effects of withdrawal, may theoretically have enhanced evolutionary vitamin D biosynthesis, it now may contribute to the relentless rise in skin cancer incidence in man.

Fat is an important macronutrient in the human diet. For patients with intestinal failure who are unable to absorb nutrients via the enteral route, intravenous lipid emulsions play a critical role in providing an energy-dense source of calories and supplying the essential fatty acids that cannot be endogenously synthesized. Over the last 50 y, lipid emulsions have been an important component of parenteral nutrition (PN), and over the last 10-15 y many new lipid emulsions have been manufactured with the goal of improving safety and efficacy profiles and achieving physiologically optimal formulations. The purpose of this review is to provide a background on the components of lipid emulsions, their role in PN, and to discuss the lipid emulsions available for intravenous use. Finally, the role of parenteral fat emulsions in the pathogenesis and management of PN-associated liver disease in PN-dependent pediatric patients is reviewed.

Intravenous lipid emulsions (IVLE) provide essential fatty acids (FA) and are a dense source of energy in parenteral nutrition (PN). Parenterally administered lipid was introduced in the 17th century but plagued with side effects. The formulation of lipid emulsions later on made it a relatively safe component for administration to patients. Many ingredients are common to all IVLE, yet the oil source(s) and its (their) percentage(s) makes them different from each other. The oil used dictates how IVLE are metabolized and cleared from the body. The FA present in each type of oil provide unique beneficial and detrimental properties. This review provides an overview of IVLE and discuss factors that would help clinicians choose the optimal product for their patients. Elucidating the characteristics of each oil source over time has resulted in an evolution of the different formulations currently available. Emulsions have gone from being solely made with soybean oil, to being combined with medium-chain triglycerides (i.e., coconut oil), olive oil, and more recently, fish oil. Unfortunately, the lipid, among other constituents in PN formulations, has been associated with the development of liver disease. Lipid-sparing or lipid-reduction strategies have therefore been proposed to avoid these complications. The ideal IVLE would reverse or prevent essential FA deficiency without leading to complications, while simultaneously providing energy to facilitate normal growth and development. Modifications in their ingredients, formulation, and dosing have made IVLE a relatively safe component alone or when added to PN formulations. The ideal emulsion, however, has yet to be developed.

A molecular genetic approach was undertaken in Saccharomyces cerevisiae to examine the functions of ARL1, encoding a G protein of the Ras superfamily. We show here that ARL1 is an important component of the control of intracellular K+. The arl1 mutant was sensitive to toxic cations, including hygromycin B and other aminoglycoside antibiotics, tetramethylammonium ions, methylammonium ions and protons. The hygromycin-B-sensitive phenotype was suppressed by the inclusion of K+ and complemented by wild-type ARL1 and an allele of ARL1 predicted to be unbound to nucleotide in vivo. The arl1 mutant strain internalized ∼25% more [14C]-methylammonium ion than did the wild type, consistent with hyperpolarization of the plasma membrane. The arl1 strain took up 30-40% less 86Rb+ than did the wild type, showing an inability to regulate K+ import properly, contributing to membrane hyperpolarity. By contrast, K+ and H+ efflux were undisturbed. The loss of ARL1 had no effect on the steady-state level or the localization of a tagged version of Trk1p. High copy suppressors of the hygromycin-B phenotype included SAP155, encoding a protein that interacts with the cell cycle regulator Sit4p, and HAL4 and HAL5, encoding Ser/Thr kinases that regulate the K+-influx mediators Trk1p and Trk2p. These results are consistent with a model in which ARL1, via regulation of HAL4/HAL5, governs K+ homeostasis in cells.