Gerald Salen

Rutgers New Jersey Medical School

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Sarah Shefer

Rutgers New Jersey Medical School

A K Batta

Veterans Biomedical Research Institute

G. Stephen Tint

Rutgers New Jersey Medical School

B. Dayal

Rutgers, The State University of New Jersey

G S Tint

Rutgers New Jersey Medical School

E.H. Mosbach

Mount Sinai Beth Israel

Ashok K. Batta

Rutgers, The State University of New Jersey

Akira Honda

The University of Tokyo

Shailendra B. Patel

University of Cincinnati

Vladimir M. Berginer

Soroka Medical Center

Cooperative Institutions

Rutgers New Jersey Medical School

Rutgers, The State University of New Jersey

Veterans Biomedical Research Institute

Harvard University

University of Tsukuba

University of California, San Francisco

Jikei University School of Medicine

Saitama Medical University

Showa University Fujigaoka Hospital

College of New Jersey

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Bile Acids: Stereospecific Side-Chain Hydroxylations in the Biosynthesis of Chenodeoxycholic Acid

Springer eBooks (1979)

E.H. Mosbach Sarah Shefer Gerald Salen

Chenodeoxycholic acid

Stereospecificity

Side chain

10.1007/978-1-4615-7064-6_16

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Citations (0)

Regulation of bile acid synthesis. Measurement of cholesterol 7 alpha-hydroxylase activity in rat liver microsomal preparations in the absence of endogenous cholesterol

Journal of Lipid Research (1981)

Sarah Shefer F. W. Cheng Susan Hauser A K Batta Gerald Salen

A rapid procedure was developed to measure hepatic cholesterol 7 alpha-hydroxylase activity in the absence of endogenous microsomal cholesterol. This method involves the preparation of an acetone powder from the microsomal fraction of rat liver that retains its cholesterol 7 alpha-hydroxylase activity and contains virtually no endogenous cholesterol. The enzyme activity is measured in the presence of labeled exogenous cholesterol as the only substrate source, and can be expressed in terms of picomoles of product formed when a simple isotope incorporation procedure is employed. Optimal assay conditions were determined and the reproducibility of the acetone powder cholesterol 7 alpha-hydroxylase assay was established. A comparison of the proposed method with the previously used double isotope derivative procedure showed comparable enzyme activities in control rats and both methods exhibited an increase in the rate of hydroxylation after cholestyramine treatment and a decrease following cholic acid treatment. In contrast, the acetone powder assay did not show any change in cholesterol 7 alpha-hydroxylase activity during cholesterol feeding. These findings suggest that bile acid feeding influences the amount of active cholesterol 7 alpha-hydroxylase present in the liver whereas cholesterol feeding does not.

Cholestyramine

Hydroxylation

Reverse cholesterol transport

10.1016/s0022-2275(20)34969-5

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Citations (59)

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Journal of Inherited Metabolic Disease (2017)

Gerald Salen Robert D. Steiner

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis caused by mutations in the cytochrome P450 CYP27A1 gene that result in production of a defective sterol 27-hydroxylase enzyme. CTX is associated with abnormally high levels of cholestanol in the blood and accumulation of cholestanol and cholesterol in the brain, tendon xanthomas, and bile. Hallmark clinical manifestations of CTX include chronic diarrhea, bilateral cataracts, tendon xanthomas, and neurologic dysfunction. Although CTX is a rare disorder, it is thought to be underdiagnosed, as presenting signs and symptoms may be nonspecific with significant overlap with other more common conditions. There is marked variability in signs and symptoms, severity, and age of onset between patients. The disease course is progressive and potentially debilitating or fatal, particularly with respect to neurologic presentations that can include intellectual disability, autism, behavioral and psychiatric problems, and dementia, among others. Treatment with chenodeoxycholic acid (CDCA; chenodiol) is the current standard of care. CDCA can help restore normal sterol, bile acid, bile alcohol, and cholestanol levels. CDCA also appears to be generally effective in preventing adverse clinical manifestations of the disease from occurring or progressing if administered early enough. Improved screening and awareness of the condition may help facilitate early diagnosis and treatment.

Cerebrotendinous Xanthomatosis

Cholestanol

Chenodeoxycholic acid

CYP27A1

10.1007/s10545-017-0093-8

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Citations (148)

Macrophage 3-hydroxy-3-methylglutaryl coenzyme a reductase activity in sitosterolemia: Effects of increased cellular cholesterol and sitosterol concentrations

Metabolism (2001)

Lien B. Nguyen Gerald Salen Sarah Shefer G. Stephen Tint Frank Ruiz

Hydroxymethylglutaryl-CoA reductase

Coenzyme A

High cholesterol

10.1053/meta.2001.26707

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Citations (13)

Cerebrotendinous Xanthomatosis

Neurologic Clinics (1989)

Vladimir M. Berginer Gerald Salen Sarah Shefer

Cerebrotendinous Xanthomatosis

Cholestanol

Chenodeoxycholic acid

10.1016/s0733-8619(18)30828-4

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Citations (39)

Microwave-induced organic reactions of bile acids: Esterification, deformylation and deacetylation using mild reagents

Steroids (1995)

B. Dayal Keshava Rao Gerald Salen

Methanesulfonic acid

Sulfonic acid

Lithocholic acid

Microwave oven

10.1016/0039-128x(95)00004-a

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Citations (30)

Ezetimibe Effectively Reduces Plasma Plant Sterols in Patients With Sitosterolemia

Circulation (2004)

Gerald Salen Klaus von Bergmann Dieter Lütjohann Peter O. Kwiterovich John P. Kane

Background— Sitosterolemia is a recessively inherited disorder that results from mutations in either ABCG5 or G8 proteins, with hyperabsorption of dietary sterols and decreased hepatic excretion of plant sterols and cholesterol. As a consequence of markedly elevated plasma and tissue sitosterol and campesterol levels, premature atherosclerosis develops. Methods and Results— In this multicenter, double-blind, randomized, placebo-controlled study, we examined whether treatment with ezetimibe, an inhibitor of cholesterol absorption, reduces plant sterol levels in patients with sitosterolemia. After a 3-week placebo run-in, 37 patients were randomized to receive placebo (n=7) or ezetimibe 10 mg/d (n=30) for 8 weeks. Sitosterol concentrations decreased by 21% ( P <0.001) in patients treated with ezetimibe compared with a nonsignificant 4% rise in those on placebo (between-group P <0.001). The reduction in sitosterol from baseline was progressive, with further decline observed at each subsequent biweekly visit. Campesterol also progressively declined, with a mean decrease after 8 weeks of 24% with ezetimibe and a mean increase of 3% with placebo treatment (between-group P <0.001). Reductions in plant sterol concentrations were similar irrespective of whether patients were undergoing concomitant treatment with resin or statin. Reductions in total sterols and apolipoprotein B were also observed. Ezetimibe was well tolerated, with no serious treatment-related adverse events or discontinuations due to adverse events being reported. Conclusions— Ezetimibe produced significant and progressive reductions in plasma plant sterol concentrations in patients with sitosterolemia, consistent with the hypothesis that ezetimibe inhibits the intestinal absorption of plant sterols as well as cholesterol, leading to reductions in plasma concentrations.

Ezetimibe

Plant sterols

10.1161/01.cir.0000116766.31036.03

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Citations (299)

Clinical presentation and treatment of familial unconjugated hypercholanaemia

Springer eBooks (2007)

A K Batta Gerald Salen D. Holmes Morton Victoria Carlton L Bull

Presentation (obstetrics)

10.1007/1-4020-2913-6_27

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Citations (0)

Absolute configuration of pentahydroxy bile alcohols excreted by patients with cerebrotendinous xanthomatosis: a circular dichroism study

Journal of Lipid Research (1978)

B. Dayal Gerald Salen G S Tint V. Toome Sarah Shefer

The absolute configurations of the C2, pentahydroxy bile alcohols present in bile and feces of two patients with cerebrotendinous xanthomatosis (CTX) were determined by circular dichroism (CD) spectroscopy.The CD spectra of 5/3-cholestane-3a,7aY, 12a,24a,25-pentol in the presence of Eu(fod)a [tris( 1,1,1,2,2,3,3-heptafluoro-7,7dimethyloctane-4,6-dionato) europium (III)] exhibited a negative Cotton effect and was assigned the 24R absolute configuration.Conversely, 5/.3-cholestane-3a,7ty,12a,24/3,25pentol showed a strong positive Cotton effect and was assigned the 24s configuration.These assignments were based upon comparison with a model compound, 5-cholestene-3/3,24(R ),25-triol, whose single-crystal X-ray structure has been determined.The importance of these data is to establish a structural mechanism for the conversion of 5/3-cholestane-3cu,7aw,12a,24S,25-pentol rather than 5/3-cholestane-3a,7a, 12a,24R ,25-pentol into cholic acid in man as well as in animals.

Cerebrotendinous Xanthomatosis

Absolute Configuration

Cholestanol

10.1016/s0022-2275(20)41556-1

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Citations (28)

Regulation of early cholesterol biosynthesis in rat liver: Effects of sterols, bile acids, lovastatin, and BM 15.766 on 3-hydroxy-3-methylglutaryl coenzyme A synthase and acetoacetyl coenzyme A thiolase activities

Hepatology (1998)

Akira Honda Gerald Salen Lien B. Nguyen Guorong Xu Stephen G. Tint

Cytosolic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase catalyzes the formation of HMG-CoA, the substrate for the rate-controlling enzyme in the cholesterol biosynthetic pathway. To explore the regulation in liver, we developed a new, accurate, and reliable reversed-phase ion-pair chromatographic assay that uses nonradioactive substrates and n -propionyl coenzyme A as an internal recovery standard. The hepatic activities were measured in rats treated with cholesterol, sitosterol, cholic acid, deoxycholic acid, ursodeoxycholic acid, cholestyramine, bile fistula, lovastatin, and BM 15.766, an inhibitor of 7-dehydrocholesterol Δ 7 -reductase, and were compared with microsomal HMG-CoA reductase and cytosolic acetoacetyl coenzyme A (AcAc-CoA) thiolase activities. HMG-CoA synthase activity was effectively suppressed in synchrony with HMG-CoA reductase activity by treatments with cholesterol (−41%, P < .05), cholic acid (−72%, P < .005), and deoxycholic acid (−62%, P < .05). However, ursodeoxycholic acid increased activity 84% ( P < .05) and intravenous sitosterol did not change activity. AcAc-CoA thiolase activities also paralleled HMG-CoA reductase and HMG-CoA synthase activities, but differences were not statistically significant. In contrast to inhibition, up-regulation of hepatic HMG-CoA synthase activities by cholestyramine, bile fistula, and lovastatin was much less than HMG-CoA reductase activities. In addition, BM 15.766 did not stimulate synthase activity, whereas lovastatin increased activity 2.4-fold. Thus, hepatic HMG-CoA synthase activity was regulated coordinately with HMG-CoA reductase, and responded more forcefully to regulatory stimuli than acetoacetyl-CoA thiolase activity but usually less than HMG-CoA reductase.

Thiolase

Lovastatin

Coenzyme A

Mevalonic acid

Hydroxymethylglutaryl-CoA reductase

Cholestyramine

CYP8B1

10.1002/hep.510270124

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Citations (18)