Lipoprotein Metabolism in Experimental Nephrosis

Abstract

In experimental nephrosis, a decrease in plasma albumin resulting from proteinuria causes a decreased in the plasma oncotic pressure. The existence of an osmoreceptor, which responds to the low oncotic pressure and produces a factor(s) that signals the liver to increase the secretion of plasma proteins, is postulated. The hyperlipidemia characteristic of the nephrotic syndrome results primarily from increased hepatic secretion of apolipoproteins and lipoproteins representing the entire density spectrum from VLDL, IDL, and LDL to HDL. Not all plasma proteins and apolipoproteins are affected to the same extent. Increased mRNA levels due to increased transcription have been shown for albumin and apolipoprotein A-1 (apoA-1). The increased secretion of VLDL, the major vehicle for triglyceride transport from the liver, appears to be due mainly to posttranscriptional events possibly related to increased lipogenesis. Once proteinuria begins, the demand for amino acids for albumin and apolipoprotein synthesis by the liver is increased. To meet this demand, protein catabolism in the peripheral tissues is increased. One manifestation of this process is a decrease in lipoprotein lipase which reduces VLDL catabolism, contributing to the sustained elevation of plasma VLDL. The spectacular overproduction of apoA-1 in nephrosis in the rat is accompanied by a decreased fractional catabolic rate (FCR), contributing to the maintenance of high levels of HDL. Urinary loss of HDL and its renal catabolism does not account for the decreased FCR. The reason for the decreased FCR is not known. Work with nephrotic rats overexpressing transgenic human apoA-1 has shown that human A-1 forms smaller HDL3-sized particles, rather than the larger HDL2 of the rat. This may contribute to the failure of HDL levels to increase in the human nephrotic syndrome. High plasma VLDL and LDL with normal or low HDL probably account for the increased incidence of coronary artery disease in the nephrotic syndrome.

The full induction of human apoprotein A-I gene expression by the experimental nephrotic syndrome in transgenic mice depends on cis-acting elements in the proximal 256 base-pair promoter region and the trans-acting factor early growth response factor 1.

“…This was directly examined, and the results are shown in Fig. 2 In general, these data are consistent with the elevations of plasma cholesterol (total and HDL) and apo A-I observed in the classical rat model (8,9). The results also demonstrated equivalent effects of expressing either of the two h-apo A-I DNA constructs on the plasma levels of cholesterol (total or HDL) and apo A-I (human or mouse) in the nephrotic mice.…”

“…As noted in the Introduction and reviewed elsewhere (8,9), the experimental nephrotic syndrome is one of the most potent known inducers of hepatic apo A-I mRNA and protein, and a large component of this induction is transcriptional (10,11). Although the cis-acting factors for the liver-specific basal expression of the h-apo A-I gene had been shown in transgenic mice (12) to reside on the 256-bp fragment 5Ј to the transcriptional start site, there are currently no data concerning the metabolic regulation in liver of induced h-apo A-I gene expression.…”

Pravastatin Treatment of Very Low Density, Intermediate Density and Low Density Lipoproteins in Hypercholesterolemia and Combined Hyperlipidemia Secondary to the Nephrotic Syndrome

“…It is generally accepted that the lipoprotein abnormalities in renal disease result from increased hepatic secretion of apo B-containing lipoproteins [5][6][7][8][9][10]. This appears to be a consistent finding in animal models of the nephrotic syndrome [2]. However, humans show variable metabolic patterns [5][6][7][8][9][10][11][12][13].…”

“…Dyslipidemia secondary to the nephrotic syndrome may consist of elevated levels of LDL alone or concomitantly elevated levels of LDL precursors, i.e., VLDL and IDL [1][2][3][4]. These lipoproteins are atherogenic and also may worsen renal function.…”

Reduced Coronary Flow Reserve and Early Diastolic Filling Abnormalities in Patients with Nephrotic Syndrome

“…[16] Furthermore, recent studies showed that triglyceride-rich proteins also have an important role. [17] Although total cholesterol, triglyceride, and LDL cholesterol levels of patients were significantly higher than those of controls, there was no correlation between CFR and lipid profiles of study subjects other than total cholesterol (r = −0.31, p = 0.02).…”