Hepatic Isoprenoid Metabolism in a Rat Model of Smith‐Lemli‐Opitz Syndrome

Abstract

Elevated (4 to 7-fold) levels of urinary dolichol and coenzyme Q and substantially longer chain lengths for urinary dolichols have been reported in Smith-Lemli-Opitz Syndrome (SLOS) patients, compared to normal subjects. We investigated the possibility of similar alterations in hepatic, nonsterol isoprenoids in a well-established rat model of SLOS. In this model, the ratio of 7-dehydrocholesterol (7DHC) to cholesterol (Chol) in serum approached 15:1; however, total sterol mass in serum decreased by >80 %. Livers from treated rats had 7DHC/Chol ratios of ~32:1, but the steady-state levels of total sterols were >40 % those of livers from age-matched (3-month-old) control animals. No significant differences in the levels of LDL receptor or HMG-CoA reductase were observed. The levels of dolichol and coenzyme Q were elevated only modestly (by 64 and 31 %, respectively; p < 0.05, N = 6) in the livers of the SLOS rat model compared to controls; moreover, the chain lengths of these isoprenoids were not different in the two groups. We conclude that hepatic isoprenoid synthesis is marginally elevated in this animal model of SLOS, but without preferential shunting to the nonsterol branches (dolichol and coenzyme Q) of the pathway and without alteration of normal dolichol chain lengths.

Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis

“…Inhibition of FDFT1, by inhibitors or siRNA, increases intracellular concentrations of FPP and GGPP. 37, 38 Furthermore, the isoprenoid alcohols, farnesol and geranylgeraniol, both of which are converted to their respective pathway intermediate diphosphates, FPP and GGPP, 28, 29 attenuated endometrial cell IL-6 and CXCL8 responses to LPS in the present study. The anti-inflammatory effect of isoprenoids has previously been demonstrated in a mouse model of mevalonate kinase deficiency, a rare disorder characterised by recurrent inflammatory episodes.…”

“…35, 36 Therefore, their depletion within the cell affects a wide range of cellular pathways, as indeed does their excessive accumulation. 37, 38 In humans, the effect of manipulating isoprenoid availability on LPS responsiveness is exemplified by reduced TLR4 expression on monocytes isolated from patients treated with statins for four weeks. Reduced TLR4 expression and LPS-mediated inflammatory responses are mediated via inhibition of protein geranylgeranylation and farnesylation, further demonstrating the importance of the interaction between cholesterol biosynthesis and innate immunity.…”

Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol‐dependent cytolysins

“…Compared with cyclodextrins or zaragozic acid, MPEX098 only reduced cholesterol in HeLa and A549 cells by 15% at most. This modest reduction may be sufficient to alter the accessible pool of cholesterol in the plasma membrane 62,67 . A potential alternative mechanism is via changes in isoprenoids because inhibiting squalene synthase increases the concentration of cellular farnesyl diphosphate and geranylgeranyl diphosphate 53,68,69 .…”

Compromised phagosome maturation underlies RPE pathology in cell culture and whole animal models of Smith-Lemli-Opitz Syndrome

“…S2A). The culture medium was then aspirated, cells were rinsed 3 times with sterile PBS, and their steady-state sterol composition was determined by reverse-phase HPLC analysis, as described in detail elsewhere [117].…”