Analysis of Glomerulosclerosis and Atherosclerosis in Lecithin Cholesterol Acyltransferase-deficient Mice

Abstract

To evaluate the biochemical and molecular mechanisms leading to glomerulosclerosis and the variable development of atherosclerosis in patients with familial lecithin cholesterol acyl transferase (LCAT) deficiency, we generated LCAT knockout (KO) mice and cross-bred them with apolipoprotein (apo) E KO, low density lipoprotein receptor (LDLr) KO, and cholesteryl ester transfer protein transgenic mice. LCAT-KO mice had normochromic normocytic anemia with increased reticulocyte and target cell counts as well as decreased red blood cell osmotic fragility. A subset of LCAT-KO mice accumulated lipoprotein X and developed proteinuria and glomerulosclerosis characterized by mesangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli. LCAT deficiency reduced the plasma high density lipoprotein (HDL) cholesterol (؊70 to ؊94%) and non-HDL cholesterol (؊48 to ؊85%) levels in control, apoE-KO, LDLr-KO, and cholesteryl ester transfer protein-Tg mice. Transcriptome and Western blot analysis demonstrated up-regulation of hepatic LDLr and apoE expression in LCAT-KO mice. Despite decreased HDL, aortic atherosclerosis was significantly reduced (؊35% to ؊99%) in all mouse models with LCAT deficiency. Our studies indicate (i) that the plasma levels of apoB containing lipoproteins rather than HDL may determine the atherogenic risk of patients with hypoalphalipoproteinemia due to LCAT deficiency and (ii) a potential etiological role for lipoproteins X in the development of glomerulosclerosis in LCAT deficiency. The availability of LCAT-KO mice characterized by lipid, hematologic, and renal abnormalities similar to familial LCAT deficiency patients will permit future evaluation of LCAT gene transfer as a possible treatment for glomerulosclerosis in LCAT-deficient states.As the key enzyme responsible for the esterification of free cholesterol present in circulating lipoproteins, LCAT 1 plays a major role in HDL metabolism (1). Several lines of evidence that include epidemiological data, transgenic animal studies, and, more recently, prospective human clinical trials (2-6) indicate that increased plasma HDL levels protect against the development of atherosclerosis. One of several proposed functions of HDL as an anti-atherogenic lipoprotein is to facilitate reverse cholesterol transport, a process by which cholesterol is transported from peripheral cells to the liver for removal from the body (7,8). LCAT may play a major role in this process by maintaining a free cholesterol gradient between peripheral cells and the HDL particle surface, thus promoting free cholesterol efflux (1). The newly generated cholesteryl esters (CE) accumulating in the HDL core may be transferred directly to the liver via whole particle and/or selective uptake (9, 10). Alternatively HDL-CE may be transferred to apoB-containing lipoproteins as a result of the activity of cholesterol ester transfer protein (CETP) (8).The important role that LCAT plays in HDL metabolism has been established by the ide...

Comment - to: F. M. Nackhoul et al. (2001) Haptoglobin phenotype and diabetic nephropathy. Diabetologia 44: 602-604

“…However, consistent manifestations have been nephropathy with marked proteinuria, corneal opacities, decreased erythrocyte life span and a variable degree of atherosclerosis. LCAT knockout mice develop glomerulosclerosis and proteinuria when fed a fat and cholesterol rich diet [5]. It is reasonable to speculate, that a yet unknown polymorphism in the LCAT gene accelerates the development of diabetes induced renal damage.…”

A Novel in Vivo Lecithin-Cholesterol Acyltransferase (LCAT)-Deficient Mouse Expressing Predominantly LpX Is Associated with Spontaneous Glomerulopathy

“…12 More recently, histopathological changes were reported in a mouse model of LCAT deficiency. 13 LCAT knockout mice in a uniform C57Bl/6 background fed a high fat/high cholesterol diet were shown to develop hyperlipidemia. However, LpX was detected in only a proportion of these mice in the plasma, in association with histological changes in the kidneys.…”

“…Despite being homogeneous in their genetic background, only a proportion of the treated animals have detectable LpX by a radio-diffusion assay and a concordance in the detection of histological lesions. 13 While suggestive, the role of LpX in the development of glomerular lesions in this model may be confounded by the co-existing dietinduced hyperlipidemia. 13 To obtain more specific in vivo evidence for the causative role of LpX, it is of great interest to create an LCAT-deficient mouse model that eliminates all other circulating lipoprotein fractions but, at the same time, accumulates significant LpX in blood.…”

“…13 While suggestive, the role of LpX in the development of glomerular lesions in this model may be confounded by the co-existing dietinduced hyperlipidemia. 13 To obtain more specific in vivo evidence for the causative role of LpX, it is of great interest to create an LCAT-deficient mouse model that eliminates all other circulating lipoprotein fractions but, at the same time, accumulates significant LpX in blood. In light of a recent report by Elferink et al, 14 demonstrating that LpX may be hepatic in origin, we hypothesize that breeding the lcat knockout mice into the sterol regulatory element binding protein (SREBP)1a transgenic mouse background may fulfill this goal.…”

From Finland to Fatland

“…Elegant murine experiments that fulfill Koch's postulates (11)(12)(13)(14)(15)(16)) support this assertion but, although highly interesting, fall outside the remits of this review. In summary, spontaneously hyperlipidemic rats and rats fed high-cholesterol diets are at increased risk of developing glomerulosclerosis, whereas lipid-lowering therapy and lipid-knockout mice are protected.…”