Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy

Abstract

Animal models link ectopic lipid accumulation to renal dysfunction, but whether this process occurs in the human kidney is uncertain. To this end, we investigated whether altered renal TG and cholesterol metabolism results in lipid accumulation in human diabetic nephropathy (DN). Lipid staining and the expression of lipid metabolism genes were studied in kidney biopsies of patients with diagnosed DN (n = 34), and compared with normal kidneys (n = 12). We observed heavy lipid deposition and increased intracellular lipid droplets. Lipid deposition was associated with dysregulation of lipid metabolism genes. Fatty acid β-oxidation pathways including PPAR-α, carnitine palmitoyltransferase 1, acyl-CoA oxidase, and L-FABP were downregulated. Downregulation of renal lipoprotein lipase, which hydrolyzes circulating TGs, was associated with increased expression of angiopoietin-like protein 4. Cholesterol uptake receptor expression, including LDL receptors, oxidized LDL receptors, and acetylated LDL receptors, was significantly increased, while there was downregulation of genes effecting cholesterol efflux, including ABCA1, ABCG1, and apoE. There was a highly significant correlation between glomerular filtration rate, inflammation, and lipid metabolism genes, supporting a possible role of abnormal lipid metabolism in the pathogenesis of DN. These data suggest that renal lipid metabolism may serve as a target for specific therapies aimed at slowing the progression of glomerulosclerosis. Animal models link ectopic lipid accumulation to renal dysfunction, but whether this process occurs in the human kidney is uncertain. To this end, we investigated whether altered renal TG and cholesterol metabolism results in lipid accumulation in human diabetic nephropathy (DN). Lipid staining and the expression of lipid metabolism genes were studied in kidney biopsies of patients with diagnosed DN (n = 34), and compared with normal kidneys (n = 12). We observed heavy lipid deposition and increased intracellular lipid droplets. Lipid deposition was associated with dysregulation of lipid metabolism genes. Fatty acid β-oxidation pathways including PPAR-α, carnitine palmitoyltransferase 1, acyl-CoA oxidase, and L-FABP were downregulated. Downregulation of renal lipoprotein lipase, which hydrolyzes circulating TGs, was associated with increased expression of angiopoietin-like protein 4. Cholesterol uptake receptor expression, including LDL receptors, oxidized LDL receptors, and acetylated LDL receptors, was significantly increased, while there was downregulation of genes effecting cholesterol efflux, including ABCA1, ABCG1, and apoE. There was a highly significant correlation between glomerular filtration rate, inflammation, and lipid metabolism genes, supporting a possible role of abnormal lipid metabolism in the pathogenesis of DN. These data suggest that renal lipid metabolism may serve as a target for specific therapies aimed at slowing the progression of glomerulosclerosis. Diabetic nephropathy (DN) is an increasing cause of morbidity and mortality worldwide and the leading cause of chronic kidney disease (CKD). Dyslipidemia in patients with type 2 diabetes is a reversible risk factor for the progression of kidney disease and cardiovascular mortality (1Rutledge J.C. Ng K.F. Aung H.H. Wilson D.W. Role of triglyceride-rich lipoproteins in diabetic nephropathy.Nat. Rev. Nephrol. 2010; 6: 361-370Crossref PubMed Scopus (99) Google Scholar, 2Cooper M.E. Jandeleit-Dahm K.A. Lipids and diabetic renal disease.Curr. Diab. Rep. 2005; 5: 445-448Crossref PubMed Scopus (22) Google Scholar). Sustained hyperglycemia in diabetes promotes FA synthesis and TG accumulation. Elevated serum TGs, FFAs, and modified cholesterol cause ectopic lipid accumulation in nonadipose tissues, including the pancreas, heart, liver, and blood vessel walls (3Schulze P.C. Myocardial lipid accumulation and lipotoxicity in heart failure.J. Lipid Res. 2009; 50: 2137-2138Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 4Li W.Y. Yao C.X. Zhang S.F. Wang S.L. Wang T.Q. Xiong C.J. Li Y.B. Zang M.X. Improvement of myocardial lipid accumulation and prevention of PGC-1α induction by fenofibrate.Mol. Med. Rep. 2012; 5: 1396-1400PubMed Google Scholar, 5Marfella R. Di Filippo C. Portoghese M. Barbieri M. Ferraraccio F. Siniscalchi M. Cacciapuoti F. Rossi F. D'Amico M. Paolisso G. Myocardial lipid accumulation in patients with pressure-overloaded heart and metabolic syndrome.J. Lipid Res. 2009; 50: 2314-2323Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 6Sharma S. Adrogue J.V. Golfman L. Uray I. Lemm J. Youker K. Noon G.P. Frazier O.H. Taegtmeyer H. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart.FASEB J. 2004; 18: 1692-1700Crossref PubMed Scopus (589) Google Scholar); this process, termed lipotoxicity, seems to play a role in the pathogenesis of DN (7Proctor G. Jiang T. Iwahashi M. Wang Z. Li J. Levi M. Regulation of renal fatty acid and cholesterol metabolism, inflammation, and fibrosis in Akita and OVE26 mice with type 1 diabetes.Diabetes. 2006; 55: 2502-2509Crossref PubMed Scopus (223) Google Scholar, 8Kim H.J. Moradi H. Yuan J. Norris K. Vaziri N.D. Renal mass reduction results in accumulation of lipids and dysregulation of lipid regulatory proteins in the remnant kidney.Am. J. Physiol. Renal Physiol. 2009; 296: F1297-F1306Crossref PubMed Scopus (99) Google Scholar, 9Bobulescu I.A. Renal lipid metabolism and lipotoxicity.Curr. Opin. Nephrol. Hypertens. 2010; 19: 393-402Crossref PubMed Scopus (224) Google Scholar, 10Jiang T. Wang X.X. Scherzer P. Wilson P. Tallman J. Takahashi H. Li J. Iwahashi M. Sutherland E. Arend L. et al.Farnesoid X receptor modulates renal lipid metabolism, fibrosis, and diabetic nephropathy.Diabetes. 2007; 56: 2485-2493Crossref PubMed Scopus (156) Google Scholar, 11Wang X.X. Jiang T. Shen Y. Adorini L. Pruzanski M. Gonzalez F.J. Scherzer P. Lewis L. Miyazaki-Anzai S. Levi M. The farnesoid X receptor modulates renal lipid metabolism and diet-induced renal inflammation, fibrosis, and proteinuria.Am. J. Physiol. Renal Physiol. 2009; 297: F1587-F1596Crossref PubMed Scopus (123) Google Scholar) and other diabetic complications. The effect of lipid accumulation in the kidney is well described in animal models of DN and obesity, where lipids accumulate in the kidney and are associated with glomerulosclerosis and tubulointerstitial injury (9Bobulescu I.A. Renal lipid metabolism and lipotoxicity.Curr. Opin. Nephrol. Hypertens. 2010; 19: 393-402Crossref PubMed Scopus (224) Google Scholar, 10Jiang T. Wang X.X. Scherzer P. Wilson P. Tallman J. Takahashi H. Li J. Iwahashi M. Sutherland E. Arend L. et al.Farnesoid X receptor modulates renal lipid metabolism, fibrosis, and diabetic nephropathy.Diabetes. 2007; 56: 2485-2493Crossref PubMed Scopus (156) Google Scholar). Although lipid deposits in glomeruli were part of Kimmelstiel and Wilson's original pathological description of nodular sclerosis (12Gröne H.J. Glomerular lipids in non-hereditary forms of glomerulopathy/glomerulonephritis.Nephrol. Dial. Transplant. 1999; 14: 1595-1598Crossref PubMed Scopus (4) Google Scholar, 13Kamanna V.S. Roh D.D. Kirschenbaum M.A. Hyperlipidemia and kidney disease: concepts derived from histopathology and cell biology of the glomerulus.Histol. Histopathol. 1998; 13: 169-179PubMed Google Scholar), renal lipotoxicity or “fatty kidney” is an unappreciated and not well documented clinical entity, partly due to the confounding multiple coexisting risk factors in DN (14Herman-Edelstein M. Thomas M.C. Thallas-Bonke V. Saleem M. Cooper M.E. Kantharidis P. Dedifferentiation of immortalized human podocytes in response to transforming growth factor-β: a model for diabetic podocytopathy.Diabetes. 2011; 60: 1779-1788Crossref PubMed Scopus (102) Google Scholar). Lipotoxicity and lipid accumulation cause podocyte dysfunction and apoptosis (7Proctor G. Jiang T. Iwahashi M. Wang Z. Li J. Levi M. Regulation of renal fatty acid and cholesterol metabolism, inflammation, and fibrosis in Akita and OVE26 mice with type 1 diabetes.Diabetes. 2006; 55: 2502-2509Crossref PubMed Scopus (223) Google Scholar, 8Kim H.J. Moradi H. Yuan J. Norris K. Vaziri N.D. Renal mass reduction results in accumulation of lipids and dysregulation of lipid regulatory proteins in the remnant kidney.Am. J. Physiol. Renal Physiol. 2009; 296: F1297-F1306Crossref PubMed Scopus (99) Google Scholar, 9Bobulescu I.A. Renal lipid metabolism and lipotoxicity.Curr. Opin. Nephrol. Hypertens. 2010; 19: 393-402Crossref PubMed Scopus (224) Google Scholar, 10Jiang T. Wang X.X. Scherzer P. Wilson P. Tallman J. Takahashi H. Li J. Iwahashi M. Sutherland E. Arend L. et al.Farnesoid X receptor modulates renal lipid metabolism, fibrosis, and diabetic nephropathy.Diabetes. 2007; 56: 2485-2493Crossref PubMed Scopus (156) Google Scholar, 11Wang X.X. Jiang T. Shen Y. Adorini L. Pruzanski M. Gonzalez F.J. Scherzer P. Lewis L. Miyazaki-Anzai S. Levi M. The farnesoid X receptor modulates renal lipid metabolism and diet-induced renal inflammation, fibrosis, and proteinuria.Am. J. Physiol. Renal Physiol. 2009; 297: F1587-F1596Crossref PubMed Scopus (123) Google Scholar, 15Nosadini R. Tonolo G. Role of oxidized low density lipoproteins and free fatty acids in the pathogenesis of glomerulopathy and tubulointerstitial lesions in type 2 diabetes.Nutr. Metab. Cardiovasc. Dis. 2011; 21: 79-85Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 16Wang Z. Jiang T. Li J. Proctor G. McManaman J.L. Lucia S. Chua S. Levi M. Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes.Diabetes. 2005; 54: 2328-2335Crossref PubMed Scopus (236) Google Scholar, 17Mishra R. Emancipator S.N. Miller C. Kern T. Simonson M.S. Adipose differentiation-related protein and regulators of lipid homeostasis identified by gene expression profiling in the murine db/db diabetic kidney.Am. J. Physiol. Renal Physiol. 2004; 286: F913-F921Crossref PubMed Scopus (75) Google Scholar). The podocyte uptake of oxidized LDL (oxLDL) is mediated mainly by the scavenger chemokine receptor CXCL16 (18Gutwein P. M.S. K. K. I.A. C. et is in podocytes and as a scavenger receptor for oxidized J. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). FA synthesis is fatty acid and while 1 is a that to and by carnitine palmitoyltransferase 1 and acyl-CoA in and expression in Lipid Res. 54: Full Text Full Text PDF PubMed Scopus Google Scholar, and of J. Physiol. Metab. 2009; 297: PubMed Scopus Google Scholar, P. H. M. of 1 fatty acid and in the J. Physiol. Metab. PubMed Scopus Google Scholar). of is a cause of metabolic as and and expression of genes in β-oxidation of to and renal in animal models with DN Z. Jiang T. Li J. Proctor G. McManaman J.L. Lucia S. Chua S. Levi M. Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes.Diabetes. 2005; 54: 2328-2335Crossref PubMed Scopus (236) Google Scholar, I. P. V. E. for diabetic J. Med. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). There is that dysregulation of regulatory proteins to the pathogenesis of DN L. Zhang T. Levi M. Role of regulatory protein 1 in of renal lipid metabolism and glomerulosclerosis in diabetes Full Text Full Text PDF PubMed Scopus Google Scholar). serve as the regulators of FA and cholesterol FA cholesterol synthesis (14Herman-Edelstein M. Thomas M.C. Thallas-Bonke V. Saleem M. Cooper M.E. Kantharidis P. Dedifferentiation of immortalized human podocytes in response to transforming growth factor-β: a model for diabetic podocytopathy.Diabetes. 2011; 60: 1779-1788Crossref PubMed Scopus (102) Google Scholar). the protein the expression of and and by induction of the F. M. C. M. J. V. L. C. J. et factor from in mice and 2012; PubMed Scopus Google Scholar). of cholesterol metabolism to lipotoxicity and lipid accumulation in Cholesterol is mediated by receptors, including scavenger receptor or Y. Y. Y. S. Y. S. T. Lipid proteins renal from fatty J. Full Text Full Text PDF PubMed Scopus Google Scholar), and LDL receptor R. Tonolo G. Role of oxidized low density lipoproteins and free fatty acids in the pathogenesis of glomerulopathy and tubulointerstitial lesions in type 2 diabetes.Nutr. Metab. Cardiovasc. Dis. 2011; 21: 79-85Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). Cholesterol that cholesterol accumulation is mediated by and Renal lipoprotein receptor expression with kidney lipid deposition in renal Metab. 19: Google Scholar, C. S. J. G. in fatty acid and an are in podocyte a J. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). The of this was to whether renal dysfunction in human DN is associated with renal lipid accumulation, lipotoxicity, and dysregulation of renal FA and cholesterol The was by the were from of kidney biopsies of patients with DN (n = and normal kidneys (n = from the pathological of the of at patients DN was by and for and and for DN glomerular and nodular and the of between and and fibrosis K. F. M. E. et of diabetic Nephrol. 2010; 21: PubMed Scopus Google Scholar). the DN renal was to clinical and in to the of other of kidney disease due the of including between the of diabetes and the of nephropathy the of diabetic were by the of diabetic with DN and the of other of in the The of and fibrosis were the of an = normal = 1 = = 2 = = and = = and were from the original pathological = 1 = 2 = = and = 1 = = 1 = 2 = increased, = increased, = 1 = 2 = = 1 = 2 = the diabetic patients and was from the The glomerular filtration was the Zhang P. F. T. et to glomerular filtration Med. 2009; PubMed Scopus Google Scholar, H. Y. J. S. J. C. K. et of X receptor and diabetic Nephrol. 2012; PubMed Scopus Google Scholar). and were to patients in the to blood were from the the of for kidney a (n = we kidney biopsies from kidney (n = and of (n = were as an and glomerulosclerosis and tubulointerstitial and of the patients are in We the to and of of progression was from of of or of data patients were in and clinical data in and of patients with DN and normal in this (n = (n = normal normal normal normal or normal normal normal normal normal normal normal normal normal glomeruli normal glomeruli normal normal normal normal fibrosis normal normal normal normal normal DN. in a was in and that The was in a of and in an was with a of 1 for a The were and with an from the The were by a to kidney and lipid staining was of kidney DN biopsies and for was in at a of 1 to the kidney in for and with a staining was to the of kidney The kidney were in in for 1 and for in the for 1 in and to The were with for 1 staining was of kidney for 2 at staining was of human kidney We were with a The was were were with We for was from of of DN kidney biopsies and normal was The was with the of increased and were by density a was to synthesis was for of to the target gene lipid and metabolic gene expression were by as described (14Herman-Edelstein M. Thomas M.C. Thallas-Bonke V. Saleem M. Cooper M.E. Kantharidis P. Dedifferentiation of immortalized human podocytes in response to transforming growth factor-β: a model for diabetic podocytopathy.Diabetes. 2011; 60: 1779-1788Crossref PubMed Scopus (102) Google Scholar), the and of for was by an to for in the of that was for in the gene expression of the target was in to the expression of an or and are are as was for were was were from kidney from DN patients and normal The clinical of the are in The DN patients a of and DN patients were to and to LDL were the in but of serum DN patients increased and increased serum and in the diabetic were and of a of but not patients were diagnosed with renal sclerosis of and sclerosis of fibrosis, and The clinical and pathological of DN from to with DN a in kidney with at a of patients in the 2 kidney in diabetic kidneys V. T. K. S. Cooper J. Miller G. H. of the low density lipoprotein receptor gene the with lipid in and 1998; 13: PubMed Scopus Google Scholar, S. F. V. M. human diabetic nephropathy the of with Metab. PubMed Scopus Google Scholar), there was increased expression of and and genes were downregulated. 2 increased significantly with increased expression of the receptor for the of including podocyte process of glomerular and We accumulation of intracellular in podocyte and and in are with lipids that well observed by in and fatty in DN the type of lipid and were in in in in the podocyte cell and in the podocytes were with while lipid We studied renal lipid accumulation by staining DN kidney and staining We lipid accumulation in glomeruli and as by staining and by staining in diabetic We for cholesterol accumulation by staining the of normal kidney and due to the that lipids we of a to in Z. Jiang T. Li J. Proctor G. McManaman J.L. Lucia S. Chua S. Levi M. Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes.Diabetes. 2005; 54: 2328-2335Crossref PubMed Scopus (236) Google Scholar, 17Mishra R. Emancipator S.N. Miller C. Kern T. Simonson M.S. Adipose differentiation-related protein and regulators of lipid homeostasis identified by gene expression profiling in the murine db/db diabetic kidney.Am. J. Physiol. Renal Physiol. 2004; 286: F913-F921Crossref PubMed Scopus (75) Google Scholar). staining increased protein expression in DN compared with normal expression was increased in DN kidneys in the of disease progression To the possible of the lipid accumulation in the kidney of the DN we the expression of genes in FA and in DN patients and compared to normal The DN increased which was associated with increased TG there was increased FA of increased FA uptake of the genes that we including and were expression of 1 not These results suggest that accumulation of is not due to increased synthesis in the of diabetic kidney The significant were in the expression of genes and that FA and were significantly in the DN kidneys was associated with a significant downregulation of and the regulators of FA L-FABP which as a in the of DN patients of L-FABP and in in type 2 diabetes PubMed Scopus Google Scholar) and is a protein for to intracellular of was downregulated. The expression of renal which hydrolyzes circulating TGs, was significantly in DN. Downregulation of renal may TG in kidney S. K. G. S. J. G. et kidney lipoprotein and renal accumulation in kidney J. Physiol. Renal Physiol. 2012; PubMed Scopus Google Scholar). protein which to play a role in in C. C. E. S. in Med. 2011; PubMed Scopus Google Scholar) and to C. protein expression is in Res. 2012; PubMed Scopus Google Scholar), was increased data suggest that increased FA uptake and FA may to TG and lipid accumulation in the diabetic of lipoprotein in the increased of to the cell by uptake of in and To the for accumulation of cholesterol in the we proteins and in cholesterol and The expression of was low in normal kidneys and significantly in the diabetic We of acetylated and which is in the uptake of as well as TG uptake The expression of the chemokine receptor in podocytes uptake of P. M.S. K. J. L. K. et and are in the of diabetic Med. 2009; 13: PubMed Scopus Google Scholar), was as part of in the of other podocyte we expression of the cholesterol and The expression of X receptor H. Y. J. S. J. C. K. et of X receptor and diabetic Nephrol. 2012; PubMed Scopus Google Scholar, E. Z. J. Wang S. M. P. J. S. et of chronic in renal by X receptor of J. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar), the receptor which cholesterol genes, was downregulated. significant in and or were between the in cholesterol synthesis data suggest that increased cholesterol uptake and cholesterol may to cholesterol accumulation in the diabetic To whether the accumulation of lipids the kidney is associated with in kidney we studied the correlation between and genes of lipid We highly significant between increased expression of acetylated LDL and the progression of DN and of the other there was a highly significant correlation between genes that FA including and There was a highly significant correlation between expression of genes that cholesterol efflux, and ABCG1, and and correlation between and genes of lipid of is correlation to to to to to to to to to to the correlation = is significant at the is significant at the is significant at the The is correlation in a correlation between of and genes in lipid of is correlation to to to to to to to to to to to to the correlation = is significant at the is significant at the The is correlation in a is significant at the is significant at the is significant at the is significant at the is significant at the lipid accumulation in the liver, heart, and is associated with lipotoxicity, inflammation, and Although animal suggest that lipotoxicity to renal dysfunction, for human DN not The of this was to whether lipids accumulate in the human diabetic kidney and to the in lipid metabolism that may associated with lipotoxicity and of renal this we that heavy lipid deposition is a of human DN. These results are with the in animal models of diabetic kidney in which accumulation of lipotoxicity, and lipid metabolism dysregulation are associated with renal X.X. Jiang T. Shen Y. Y. Miyazaki-Anzai S. H. C. Scherzer P. Lewis L. et nephropathy is by farnesoid X receptor and by farnesoid X receptor in a type 1 diabetes 2010; PubMed Scopus Google Scholar). diabetic patients renal and renal and lipids and cholesterol are not in and in of a to from Thomas K. of human diabetic kidney 2011; 60: PubMed Scopus Google Scholar) and to kidney diabetic patients in to other to the a of DN biopsies that of DN. a of we the and that from a of patients for kidney clinical and the of renal and data with gene expression, the that we to biopsies there is of kidney of diagnosed or from but the of this is that the patients were and in and the or We clinical and that are not in Lipids are not normal of kidney biopsies for in the of cholesterol lipids in the process of are in which lipids are as a of and cholesterol by protein Y. Y. Y. S. Y. S. T. Lipid proteins renal from fatty J. Full Text Full Text PDF PubMed Scopus Google Scholar). These of TGs, which by for β-oxidation to the cell with P.C. T. J. Myocardial 55: Full Text Full Text PDF PubMed Scopus Google Scholar). for which is the protein of is possible in kidney and to lipid accumulation. of was the of lipid accumulation in renal from diabetic as by lipid staining including and we the of by in glomerular and in of progression of DN kidneys and are in We of staining and staining in diabetic compared with normal in kidneys the of to process may to the of in liver, to T. T. K. M. T. T. S. T. et of is associated with the of 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). animal models for kidney including metabolic M. Wang as Nephrol. 2011; PubMed Scopus Google Scholar), chronic Y. R. K. P. Y. K. M. of fatty acid metabolism in the kidney of J. Physiol. Renal Physiol. 2012; PubMed Scopus Google Scholar), chronic renal renal and kidney injury Y. R. K. P. Y. K. M. of fatty acid metabolism in the kidney of J. Physiol. Renal Physiol. 2012; PubMed Scopus Google Scholar), accumulation of lipids in the renal which an part in the progression of renal to and intracellular lipid accumulation is by a between the and or of and To possible of TG accumulation in the we the expression of that are regulators of FA metabolism in and expression in Lipid Res. 54: Full Text Full Text PDF PubMed Scopus Google Scholar, and of J. Physiol. Metab. 2009; 297: PubMed Scopus Google Scholar, P. H. M. of 1 fatty acid and in the J. Physiol. Metab. PubMed Scopus Google Scholar), increased uptake and expression of of β-oxidation and The of and and and were and with the in in lipid metabolism possible for intracellular TG accumulation in diabetic To of cholesterol accumulation in the we genes that are regulators of cholesterol cholesterol efflux, and cholesterol uptake lipoprotein We in lipoprotein scavenger receptor and These were with the cholesterol receptor in was to There was downregulation of cholesterol genes, the and that with in cholesterol metabolism gene expression that increased cholesterol and cholesterol may suggest possible for intracellular cholesterol accumulation in the diabetic of of and and target was in human the in models X.X. Jiang T. Shen Y. Y. Miyazaki-Anzai S. H. C. Scherzer P. Lewis L. et nephropathy is by farnesoid X receptor and by farnesoid X receptor in a type 1 diabetes 2010; PubMed Scopus Google Scholar), where of DN M. models of diabetic nephropathy in mice models of type 2 to human Res. 2012; PubMed Scopus Google Scholar). that we observed in the diabetic human kidney not data from animal due to the that in the human kidney to the diabetic but is possible that in the of hyperglycemia there is increased in the data from other human diabetic kidney gene expression profiling V. T. K. S. Cooper J. Miller G. H. of the low density lipoprotein receptor gene the with lipid in and 1998; 13: PubMed Scopus Google Scholar, S. F. V. M. human diabetic nephropathy the of with Metab. PubMed Scopus Google Scholar, Thomas K. of human diabetic kidney 2011; 60: PubMed Scopus Google Scholar) and described in human as a of T. T. K. M. T. T. S. T. et of is associated with the of 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). is an of and in the by the podocyte to the was as a of in C. C. E. S. in Med. 2011; PubMed Scopus Google Scholar). We of in DN kidneys that to serum as well as The of lipotoxicity or of and We a correlation between and expression of lipid metabolic genes and 1, a role in the progression of DN and in lipid and lipoprotein metabolism Wang Y. C. fatty acid and in the Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. C. Downregulation of X in kidney and by and Lipid Res. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, M.S. C. of receptor and in the Lipid Res. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, C. fatty acid and in the Lipid Res. 2009; 50: Full Text Full Text PDF PubMed Scopus Google Scholar, C. the expression of Res. PubMed Scopus Google Scholar) in animal models that the we in human a possible role for in altered lipid metabolism, the serum lipid is well we for lipid accumulation and lipotoxicity in human of and cholesterol in human kidney in diabetes from a between lipid uptake lipid and may in in lipid metabolism and lipid accumulation We significant correlation between lipid metabolism, inflammation, podocyte dysfunction, fibrosis, and the of lipid accumulation in human kidney and possible lipotoxicity may serve as a target for specific therapies aimed to the progression of glomerulosclerosis in DN. The Miller for and from acetylated LDL acyl-CoA differentiation-related angiopoietin-like protein protein chronic kidney disease carnitine palmitoyltransferase 1 diabetic nephropathy glomerular filtration lipid LDL receptor oxidized LDL as X receptor oxidized LDL 1 regulatory protein