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.