Lipotoxicity in diabetic nephropathy: the potential role of fatty acid oxidation.

Cellular toxicity mediated by lipids (lipotoxicity) has been implicated in the pathophysiology of metabolic syndrome and diabetes mellitus. Genetic analyses now implicate lipotoxicity in susceptibility to type 2 diabetes mellitus-associated nephropathy (T2DN), a pathway that had previously been unexplored. A genome-wide association study in Japanese patients identified a single nucleotide polymorphism in the acetyl-CoA carboxylase β (ACACB) gene associated with T2DN. Replication analyses suggest that this same polymorphism may be a diabetic nephropathy risk allele in other ethnic groups. The ACACB gene (also called ACC2 or acetyl-CoA carboxylase 2) plays a critical role in intracellular fatty acid (FA) oxidation. This manuscript reviews the physiology of FA metabolism and adverse cellular effects that can result from dysregulation of this process. It is hypothesized that glomerular and tubular dysfunction can be induced by increases in intracellular FA concentrations, a process that may be enabled by genetic risk variants. This novel glucolipotoxicity hypothesis in T2DN warrants further investigation.

[1]  C. Langefeld,et al.  The acetyl-coenzyme A carboxylase beta (ACACB) gene is associated with nephropathy in Chinese patients with type 2 diabetes. , 2010, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[2]  R. Kawamori,et al.  Overexpression of acetyl-coenzyme A carboxylase beta increases proinflammatory cytokines in cultured human renal proximal tubular epithelial cells , 2010, Clinical and Experimental Nephrology.

[3]  Xueying Zhao,et al.  Fenofibrate attenuates tubulointerstitial fibrosis and inflammation through suppression of nuclear factor-κB and transforming growth factor-β1/Smad3 in diabetic nephropathy , 2010, Experimental biology and medicine.

[4]  J. Ix,et al.  Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK. , 2010, Journal of the American Society of Nephrology : JASN.

[5]  J. Gerich.  Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications , 2010, Diabetic medicine : a journal of the British Diabetic Association.

[6]  T. Hansen,et al.  A Single Nucleotide Polymorphism within the Acetyl-Coenzyme A Carboxylase Beta Gene Is Associated with Proteinuria in Patients with Type 2 Diabetes , 2010, PLoS genetics.

[7]  A. Saito,et al.  Molecular Mechanisms of Receptor-Mediated Endocytosis in the Renal Proximal Tubular Epithelium , 2009, Journal of biomedicine & biotechnology.

[8]  C. Folmes,et al.  Myocardial fatty acid metabolism in health and disease. , 2010, Physiological reviews.

[9]  T. Doi,et al.  Phosphorylation of nephrin triggers its internalization by raft-mediated endocytosis. , 2009, Journal of the American Society of Nephrology : JASN.

[10]  W. Ratnayake,et al.  Fat and Fatty Acid Terminology, Methods of Analysis and Fat Digestion and Metabolism: A Background Review Paper , 2009, Annals of Nutrition and Metabolism.

[11]  Keith C. Norris,et al.  Renal mass reduction results in accumulation of lipids and dysregulation of lipid regulatory proteins in the remnant kidney. , 2009, American journal of physiology. Renal physiology.

[12]  S. Sturley,et al.  Saturated with fat: new perspectives on lipotoxicity , 2009, Current opinion in clinical nutrition and metabolic care.

[13]  B. Schermer,et al.  Lipid-protein interactions along the slit diaphragm of podocytes. , 2009, Journal of the American Society of Nephrology : JASN.

[14]  S. Pennathur,et al.  CD36 regulates oxidative stress and inflammation in hypercholesterolemic CKD. , 2009, Journal of the American Society of Nephrology : JASN.

[15]  S. Schinner.  Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes , 2009 .

[16]  S. Schinner,et al.  Effects of Intensive Glucose Lowering in Type 2 Diabetes , 2009 .

[17]  T. Ishimitsu,et al.  Association of metabolic syndrome with urinary albumin excretion, low-grade inflammation, and low glomerular filtration rate among non-diabetic Japanese subjects. , 2009, Internal medicine.

[18]  S. Fazio.  More Clinical Lessons from the FIELD Study , 2009, Cardiovascular Drugs and Therapy.

[19]  J. Nunnelee.  Review of an article: The ADVANCE Collaborative Group. (2008). Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. NEJM 2008;358:2560-2572. , 2008 .

[20]  Diederick Grobbee,et al.  Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. , 2008, The New England journal of medicine.

[21]  O. Pedersen,et al.  Effect of a multifactorial intervention on mortality in type 2 diabetes. , 2008, The New England journal of medicine.

[22]  Y. Terauchi,et al.  Role of altered renal lipid metabolism in the development of renal injury induced by a high-fat diet. , 2007, Journal of the American Society of Nephrology : JASN.

[23]  T. Jiang,et al.  Farnesoid X Receptor Modulates Renal Lipid Metabolism, Fibrosis, and Diabetic Nephropathy , 2007, Diabetes.

[24]  M. Cooper,et al.  AGE, RAGE, and ROS in diabetic nephropathy. , 2007, Seminars in nephrology.

[25]  S. Prabhakar,et al.  Lipids and diabetic nephropathy , 2006, Current diabetes reports.

[26]  M. Chalfie,et al.  Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels , 2006, Proceedings of the National Academy of Sciences.

[27]  A. Sugawara,et al.  Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor alpha. , 2006, Diabetes.

[28]  A. Chait,et al.  IGF-1 induces rat glomerular mesangial cells to accumulate triglyceride. , 2006, American journal of physiology. Renal physiology.

[29]  P Glasziou,et al.  Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial , 2005, The Lancet.

[30]  T. Jiang,et al.  Diet-induced Obesity in C57BL/6J Mice Causes Increased Renal Lipid Accumulation and Glomerulosclerosis via a Sterol Regulatory Element-binding Protein-1c-dependent Pathway* , 2005, Journal of Biological Chemistry.

[31]  J. McManaman,et al.  Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes. , 2005, Diabetes.

[32]  L. Gesualdo,et al.  Pathogenetic mechanisms of diabetic nephropathy. , 2005, Journal of the American Society of Nephrology : JASN.

[33]  Kumar Sharma,et al.  Multiple Metabolic Hits Converge on CD36 as Novel Mediator of Tubular Epithelial Apoptosis in Diabetic Nephropathy , 2005, PLoS medicine.

[34]  Y. Guan.  Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome. , 2004, Journal of the American Society of Nephrology : JASN.

[35]  T. Benzing,et al.  Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. , 2003, Human molecular genetics.

[36]  J. Schaffer,et al.  Lipotoxicity: when tissues overeat , 2003, Current opinion in lipidology.

[37]  Oluf Pedersen,et al.  Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. , 2003, The New England journal of medicine.

[38]  M. Matsuda,et al.  Apolipoprotein E genetic polymorphism, remnant lipoproteins, and nephropathy in type 2 diabetic patients. , 2002, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[39]  F. Gonzalez,et al.  Identification of functions of peroxisome proliferator-activated receptor alpha in proximal tubules. , 2002, Journal of the American Society of Nephrology : JASN.

[40]  Lijun Sun,et al.  Role of Sterol Regulatory Element-binding Protein 1 in Regulation of Renal Lipid Metabolism and Glomerulosclerosis in Diabetes Mellitus* , 2002, The Journal of Biological Chemistry.

[41]  M. Saleem,et al.  Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. , 2001, The Journal of clinical investigation.

[42]  A. Miettinen,et al.  Involvement of lipid rafts in nephrin phosphorylation and organization of the glomerular slit diaphragm. , 2001, The American journal of pathology.

[43]  M. Cooper,et al.  Potential influence of lipids in diabetic nephropathy: insights from experimental data and clinical studies. , 2000, Diabetes & metabolism.

[44]  W. Keane,et al.  The role of lipids in renal disease: future challenges. , 2000, Kidney international. Supplement.

[45]  G. Shulman,et al.  On Diabetes: Insulin Resistance Cellular Mechanisms of Insulin Resistance , 2022 .

[46]  G. Schreiner.  Renal toxicity of albumin and other lipoproteins , 1995, Current opinion in nephrology and hypertension.

[47]  J. S. Lee,et al.  Intraglomerular lipid deposition in routine biopsies. , 1991, Clinical nephrology.

[48]  P. Kimmelstiel,et al.  Intercapillary Lesions in the Glomeruli of the Kidney. , 1936, The American journal of pathology.