lipotoxicity and its complications
,1,* Elham zadehashem
,2 Ata kabudari
1. Faculty of Veterinary Medicine,Urmia University
2. Faculty of Veterinary Medicine,Urmia University
3. Faculty of Veterinary Medicine,Urmia University
In the last few decades a change in lifestyle has led to an alarming increase in the prevalence of obesity and obesity-associated complications at epidemic rate in the developed and developing world. the reasons for the increasing prevalence of obesity are multifaceted, but social and environmental factors in combination with genetic predisposition are leading to overall positive energy balance. the excess calories of these patients are stored as triglycerides in adipose tissue, but also may accumulate ectopically in other organs, such as liver , kidneys ,heart ,bone marrow and pancreatic β cells which contributes to the progression of metabolic diseases via cellular injury, inflammation and impairs normal cell signaling leading to cell dysfunction, a process termed lipotoxicity.obese patients are at increased risk of developing hypertension, heart disease, renal disease, insulin resistance, dyslipidemia, type 2 diabetes, fatty liver and a range of other disorders, generally known as the metabolic syndrome, as well as several types of cancer. lipotoxicity is a pathogenic mechanism and is relevant for the metabolic syndrome
In obesity, chronically high levels of serum tg and ffas contribute to intracellular accumulation of fatty acids and their derivatives, such as ceramides and diacylglycerol (dag) in many non-adipose tissues. excess carbohydrate, which cannot be converted to glycogen, is converted to triglyceride (tg) and stored in adipose tissue. serum free fatty acids (ffas) are liberated by lipolysis of tg. lipotoxicity in glomeruli is also involved in the initiation of glomerular damage related to obesity and type 2 diabetes mellitus. recently, the evidence suggests that renal lipid accumulation leads to glomerular damage and, more specifically, produces dysfunction in podocytes, key cells that compose and maintain the glomerular filtration barrier. there is also growing evidence that ectopic lipid accumulation is associated with structural and functional changes of mesangial cells, podocytes, and proximal tubular cells. the mitochondrial b-oxidation of free fatty acids (ffa) is a major source of renal atp production, particularly in proximal tubular cells (ptc), which have a high energy demand. proximal tubular cells take up circulating ffas dissociated from albumin through specific membrane proteins, such as fatty acid translocase (cd36) and fatty acid-binding protein.
In addition, proximal tubular cells retrieve albumin- bound ffas from the glomerular filtrate by receptor-mediated albumin endocytosis. there is a close association between autophagy and lipotoxicity in the kidney proximal tubule, as lipidoverload stimulates autophagy and elevated autophagy plays a crucial role in counteracting lipotoxicity through mitochondrial quality control. cryptoxanthin, an antioxidant carotenoid, prevented and reversed insulin resistance and steatohepatitis in a lipotoxic model of nafld by suppressing excessive lipid accumulation and peroxidation.cd36 allows for the buildup of intracellular fatty acids which can cause lipotoxicity, and targeting cd36 may be useful in the treatment of renal disease.these data suggest that renal lipid metabolism and cytoskeleton rearrangements may serve as a target for specific therapies aimed at slowing the progression of podocyte failure during metabolic syndrome . loss of hepatic biliverdin reductase a (bvra) causes fat accumulation in livers of mice on a high-fat diet. bvra protects mouse proximal tubule cells from palmitic acid-induced lipotoxicity and increases the energy state of the cell.further studies to determine the importance of bvra in protecting proximal tubule cells in vivo from lipotoxic injury are needed.
Activating bvra in the proximal tubule may be a novel therapeutic target to protect the kidney against obesity- induced renal damage. 1- methylnicotinamide (1-mna) is a precursor of nicotinic acid, a vitamin that exist in certain foods, such as green tea leaves and celery.treatment with 1-mnasignificantly inhibited palmitate-albumin-induced production of mitochondrial superoxide ,ffa-related oxidative stress and ameliorated lipotoxicity mediated renal tubular cell damage. these results suggest that treatment with 1-mna ameliorates palmitate-albumin-induced apoptosis and necrosis by suppressing mitochondrial oxidative stress in proximal tubular cells, without affecting the mrna levels of antioxidant enzymes and the intracellular concentration of nad and nadh.
Lipotoxicity, obesity, metabolic syndrome, oxidative stress