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ABSTRACT: Deletion of the acyltransferases responsible for triglyceride and steryl ester synthesis in Saccharomyces cerevisiae serves as a genetic model of diseases where lipid overload is a component. The yeast mutants lack detectable neutral lipids and cytoplasmic lipid droplets and are strikingly sensitive to unsaturated fatty acids. Expression of human diacylglycerol acyltransferase 2 in the yeast mutants was sufficient to reverse these phenotypes. Similar to mammalian cells, fatty acid-mediated death in yeast is apoptotic and presaged by transcriptional induction of stress-response pathways, elevated oxidative stress, and activation of the unfolded protein response. To identify pathways that protect cells from lipid excess, we performed genetic interaction and transcriptional profiling screens with the yeast acyltransferase mutants. We thus identified diacylglycerol kinase-mediated phosphatidic acid biosynthesis and production of phosphatidylcholine via methylation of phosphatidylethanolamine as modifiers of lipotoxicity. Accordingly, the combined ablation of phospholipid and triglyceride biosynthesis increased sensitivity to saturated fatty acids. Similarly, normal sphingolipid biosynthesis and vesicular transport were required for optimal growth upon denudation of triglyceride biosynthesis and also mediated resistance to exogenous fatty acids. In metazoans, many of these processes are implicated in insulin secretion thus linking lipotoxicity with early aspects of pancreatic beta-cell dysfunction, diabetes, and the metabolic syndrome.
Journal of Biological Chemistry 09/2009; 284(45):30994-1005. · 4.77 Impact Factor
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ABSTRACT: Esterification of sterols, fatty acids and other alcohols into biologically inert forms conserves lipid resources for many cellular functions. Paradoxically, the accumulation of neutral lipids such as cholesteryl ester or triglyceride, is linked to several major disease pathologies. In a remarkable example of genetic expansion, there are at least eleven acyltransferase reactions that lead to neutral lipid production. In this review, we speculate that the complexity and apparent redundancy of neutral lipid synthesis may actually hasten rather than impede the development of novel, isoform-specific, therapeutic interventions for acne, type 2 diabetes, obesity, hyperlipidemia, fatty liver disease, and atherosclerosis.
AJP Gastrointestinal and Liver Physiology 05/2007; 292(4):G953-7. · 3.43 Impact Factor
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Journal of Pediatric Gastroenterology and Nutrition 12/2004; 39(5):552-6. · 2.30 Impact Factor
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ABSTRACT: Recognition that specific nutrients can be beneficial when consumed in amounts above the accepted daily requirements has provided a major impetus for the critical examination of dietary approaches with single or multiple nutrient supplements chosen to modulate the inflammatory response, enhance immune function, or improve the blood-gut barrier. Patients suffering the effects of hypercatabolism caused by surgery, cancer, or extensive burns are prime candidates for immunonutrition, as the intervention has come to be known, as are immunosuppressed patients with the human immunodeficiency virus or other overwhelming infections. This review focuses on key nutrients used in clinical trials for which a body of information on the mode of action and metabolic pathways is available. The topics covered include the amino acids, glutamine and arginine; omega-3 fatty acids, eicosapentaenoic acid and docosahexanoic acid; vitamin A; and zinc. Lastly, we address the area of pre- and probiotics and how "friendly" microorganisms are being incorporated into therapeutic regimens aimed at sustaining health. The use of immunonutrition requires judicious consideration of the potential undesirable effects of certain additives in clinical settings where enhanced immune responsiveness can translate into tissue damage and altered mucosal defenses.
Current Opinion in Gastroenterology 12/2002; 18(6):717-22. · 4.19 Impact Factor
