Mevalonate metabolism in pregnant rats

The contribution of the cholesterol biosynthetic pathway to intermediary metabolism and cell function

“…Hepatic cholesterogenesis was significantly increased (44000+5200d.p.m./h per g compared with the control incorporation of 32000 + 1500d.p.m./h per g, P< 0.01), accounting for 3% of the administered dose compared with 2% in the control rats, and was associated with increased appearance of radiolabelled sterols in the serum (14000 ± 4700d.p.m./ml compared with 9000+1400d.p.m./ml). Thus, we confirm the observation that impaired kidney function leads to increased hepatic use of mevalonate for sterol production but the physiological relevance of the association between decreased renal clearance of mevalonate and hypercholesterolaemia in kidney disease and during pregnancy (Feingold et al, 1980) has yet to be established. chylomicron remnants although LD lipoprotein receptor synthesis can also be induced, for example, by 17a-ethinyl oestradiol (Kovanen et al, 1979) and by cholestyramine in rabbits (Slater et al, 1980).…”

“…Whilst in general the extrahepatic tissues may be dependent, in part, on substrate obtained from the liver, the kidney appears to have a specific role in the clearance of blood mevalonate. Circulating mevalonate is mainly of hepatic origin and is metabolized principally by the kidney (Edmond et al, 1976;Feingold et al, 1980), the renal extraction rate being in the range 114-720pmol/min for two kidneys (Kopito & Brunengraber, 1980). In addition to rapid metabolism to sterols, mevalonate is converted to CO2 and fatty acid via 3,3-dimethylallylpyrophosphate and trans-3-methylglutaconyl-CoA (Fogelman et al, 1975).…”

Early Embryonic Lethality Caused by Targeted Disruption of the 3-Hydroxy-3-methylglutaryl-CoA Reductase Gene

“…The fact that growth arrest of blastocysts by compactin and teratogenic effects of mevinolin were readily reversed by administered mevalonate indicates that they were due to end-product deficiency and not to precursor build-up. At mid and late gestation, mevalonate was demonstrated to cross the maternal-fetal barrier (45), suggesting that maternally derived mevalonate might be utilized by later-stage developing embryos. Although mevalonate in early stage embryos seems to be permeable into embryonic cells from intrauterine environment, the cellular amount of mevalonate might be in tight control to support proper peri-implantation development, making its unregulated supplementation to the dams invalid.…”

Plasma mevalonate and its importance in nephrology

“…The regulation of circulating MVA by sterol and shunt pathways is a complex interplay of dietary [15,16], sex hormones [17][18][19][20], thyroid hormone [21], and insulin [22]. The relationship between plasma MVA and a number of other key metabolic and physiological processes provides indirect evidence for the importance of the MVA pathway and its association with plasma MVA levels.…”