title: Lipotoxicity.
abstract: Excess fatty acids accompanied by triglyceride accumulation in parenchymal cells of multiple tissues including skeletal and cardiac myocytes, hepatocytes, and pancreatic beta cells results in chronic cellular dysfunction and injury. The process, now termed lipotoxicity, can account for many manifestations of the 'metabolic syndrome'. Most data suggest that the triglycerides serve primarily a storage function with toxicity deriving mainly from long-chain nonesterified fatty acids (NEFA) and their products such as ceramides and diacylglycerols. In the kidney, filtered NEFA carried on albumin can aggravate the chronic tubule damage and inflammatory phenotype that develop during proteinuric states and lipid loading of both glomerular and tubular cells is a common response to renal injury that contributes to progression of nephropathy. NEFA-induced mitochondrial dysfunction is the primary mechanism for energetic failure of proximal tubules during hypoxia/reoxygenation and persistent increases of tubule cell NEFA and triglycerides occur during acute renal failure in vivo in association with downregulation of mitochondrial and peroxisomal enzymes of beta oxidation. In acute renal failure models, peroxisome proliferator-activated receptor alpha ligand treatment can ameliorate the NEFA and triglyceride accumulation and limits tissue injury likely via both direct tubule actions and anti-inflammatory effects. Both acute and chronic kidney disease are associated with systemic manifestations of the metabolic syndrome.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Veterans Affairs Ann Arbor Healthcare System and University of Michigan, Ann Arbor, Michigan, USA. wnberg@umich.edu
authors.forename: J M
authors.initials: JM
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D005227:Fatty Acids / Q000009:adverse effects* / Q000378:metabolism; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D024821:Metabolic Syndrome / Q000503:physiopathology*; D051437:Renal Insufficiency / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D005227:Fatty Acids