Raised plasma cholesterol precursors in patients with gut resections.

Abstract

SUMMARY Cholesterol synthesis, faecal bile acids and neutral sterols, and plasma squalene and free and esterified cholesterol precursor sterols concentrations were studied in patients with previous ileal resection (n=30) or jejunoileal bypass (n=9) to elucidate the responses of different cholesterol precursors to enhanced cholesterol synthesis induced by cholesterol and bile acid malabsorption. A subgroup of seven resection patients without fat and bile acid malabsorption served as controls. Of the resection patients, eight had a pure bile acid malabsorption and 15 a combination of fat, bile acid, and modest cholesterol malabsorption. In the patients with jejunoileal bypass, cholesterol and fat absorption was greatly decreased in addition to bile acid malabsorption. The overall cholesterol synthesis was associated with proportionately increased plasma contents of free (and, less consistently, esterified) methyl sterols, the most marked increase, up to 18 times, being recorded for free and esterified lathosterols. The concentrations of the precursor sterols were similarly increased in the subjects with bile acid and cholesterol malabsorption, the two lathosterols showing the highest correlations with the overall cholesterol synthesis (r=0.820-0941). In the subjects with jejunoileal bypass cholesterol malabsorption effectively regulated cholesterol synthesis and the precursor levels. Gut exclusions large enough to cause cholesterol and/or bile acid malabsorption activate cholesterol synthesis leading to a proportional elevation in the plasma concentrations of cholesterol precursors, especially in those of lathosterols and free methyl sterols. Determination of the plasma concentration of total lathosterol by a single gas-chromatographic run is a suitable method for rapid screening of clinically significant cholesterol and bile acid malabsorption.

Stimulation of cholesterol synthesis and hepatic lipogenesis in patients with severe malabsorption

“…The large increase in cholesterol synthesis is consistent with previous reports of raised concentrations in the plasma of cholesterol precursors (1,4,5) and of increased activity of hepatic HMG-CoA reductase (4) in patients with ileum resection. The initial stimulus is considered to be the malabsorption of bile acids resulting in the loss of repression by Farnesoid X receptor (FXR) of the expression of CYP7A1 (22,23) in order to compensate for bile acids malabsorption by an increased synthesis of cholesterol.…”

“…The initial stimulus is considered to be the malabsorption of bile acids resulting in the loss of repression by Farnesoid X receptor (FXR) of the expression of CYP7A1 (22,23) in order to compensate for bile acids malabsorption by an increased synthesis of cholesterol. This increased use of cholesterol for bile acids synthesis induces an increase in hepatic cholesterol synthesis (1,4,5) and also in the uptake of cholesterol-rich lipoproteins by the liver (4), which then results in a decrease of plasma cholesterol concentration. This picture is overall comparable to the one observed in mice overexpressing CYP7A1 in the liver (24).…”

“…The decrease in plasma cholesterol has been ascribed to the interruption of the entero-hepatic cycle of bile acids (2)(3)(4), resulting (in addition to a possible decrease in the absorption of cholesterol) (2) in an enhanced synthesis of bile acids from cholesterol (1). This increased utilization of cholesterol for bile acid synthesis would itself lead then to a stimulation of the uptake by liver of cholesterol-rich lipoproteins and of hepatic cholesterol synthesis (1,4,5). However, to our knowledge, cholesterol synthesis has not been directly measured in humans with intestinal failure, except in one report showing an increased cholesterol turnover rate in two patients with total enterectomy and bile acid diversion (6).…”

Lathosterol and other noncholesterol sterols during treatment of hypercholesterolemia with lovastatin alone and with cholestyramine or guar gum.

“…4041 However, the serum ratios are also inversely related to biliary cholesterol secretion and fecal output of endogenous steroids. 40 - 47 In patients with gut resections and cholesterol and fat malabsorption, serum campesterol and sitosterol levels in relation to the cholesterol level are low, 37 -39 whereas in patients with ileal bypass the values are high. 47 The increase in plant sterol to cholesterol ratios of the present study during lovastatin treatment could be due to lowered biliary secretion caused by reduced cholesterol synthesis.…”

Aberrant pathways in the late stages of cholesterol biosynthesis in the rat: origin and metabolic fate of unsaturated sterols relevant to the Smith-Lemli-Opitz syndrome

“…Similar accumulation of the ⌬ 5,7 , ⌬ 5,8 (29,30), and ⌬ 8 (30) sterols has been reported in a rat model after treatment with AY-9944, a ⌬ 7 reductase inhibitor. Elevated or abnormal levels of other cholesterol precursors have also been observed in gonadal tissue (5), pregnant women (31), and subjects with cerebrotendinous xanthomatosis (32), chondrodysplasia punctata (CDP) (33,34), and gut resection (35). Some of the deleterious effects of SLOS have been ascribed to oxygenated derivatives of noncholesterol sterols (27), and the ⌬ 5,7 sterol (or an oxygenated derivative thereof) is evidently capable of regulating cholesterol biosynthesis (36).…”