Impaired renal mevalonate metabolism in nephrotic syndrome: a stimulus for increased hepatic cholesterogenesis independent of GFR and hypoalbuminemia.
Increased hepatic lipogenesis in the nephrotic syndrome is not adequately explained by hypoalbuminemia. In this disorder an enhanced delivery of the cholesterol precursor mevalonic acid (MVA) to the liver may be an unidentified stimulus to cholesterogenesis. Since the kidneys are the major site of mevalonate excretion and metabolism by either the sterol or nonsterol shunt pathways, an impairment of any of these metabolic alternatives could result in redistribution of mevalonate to the liver. Male Sprague-Dawley rats rendered nephrotic by puromycin aminonucleoside had their kidneys perfused with Krebs-Henseleit-bicarbonate buffer containing albumin, glucose and 5-14C-MVA. The number five carbon label was utilized so that any 14CO2 produced would represent mevalonate shunt pathway activity. The isolated perfused kidney was used to eliminate confounding variables. In eight control kidneys perfused for 2 hr 62 +/- 2% of the MVA was removed from the perfusate compared to 50 +/- 2% in five nephrotic kidneys (p less than .006). Urinary MVA recovery was 22 +/- 2% in controls. 15 +/- 1% in nephrotics (p less than .05). The incorporation of 14C into renal tissue lipids was not different in the two groups. Recovery of 14CO2 was two times greater in controls than in nephrotics (p less than .006). Inulin clearance per gram of kidney and sodium reabsorption were similar for the two groups. Isolated perfused kidneys from nephrotic rats metabolize MVA abnormally such that less is excreted, less is oxidized, and more is available for recirculation to the liver. This occurs independently of hypoalbuminemia, a change in glomerular filtration rate, or an overt histo-pathologic lesion. These events create an environment for increased hepatic cholesterol synthesis.
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D005919:Glomerular Filtration Rate; D007444:Inulin / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism*; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000378:metabolism*; D011692:Puromycin Aminonucleoside; D051381:Rats; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism
D012709:Serum Albumin; D011692:Puromycin Aminonucleoside; D007444:Inulin; D002784:Cholesterol; D012964:Sodium; D008798:Mevalonic Acid