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.
Bile acid sequestrants have been shown to lower glucose levels in patients with type 2 diabetes. To investigate how colesevelam (CL) HCl improves hyperglycemia, studies were conducted in diet-induced ...obesity (F-DIO) rats, which develop insulin resistance when fed a high-energy (high fat/high sucrose) diet (HE). The rats were fed HE; HE + 2% CL; HE + 0.02% SC-435 (SC), an apical sodium-dependent bile acid transporter inhibitor; and regular chow (controls). After 4 wk of treatment, both in the HE group and the SC + HE group, plasma glucose and insulin levels remained elevated compared with baseline values throughout an oral glucose tolerance test (OGTT). In contrast, in the CL + HE group, plasma glucose levels returned to baseline by the end of the test, and insulin peaked in 15-30 min and then returned to baseline. CL induced release of glucagon-like peptide-1 (GLP-1) because the area under the curve of plasma total GLP-1 in the CL + HE group was significantly greater than in the HE group during the OGTT. Bile acid concentrations in the portal blood did not decrease in the HE group but declined significantly both in the CL + HE and SC + HE groups with reduced farnesoid X receptor activation compared with controls. We concluded that CL reduces plasma glucose levels by improving insulin resistance in this rat model. It is unlikely that the improvement is attributable to decreased bile acid flux to the liver but is likely secondary to induced GLP-1 secretion, which improves insulin release.
Phytosterolemia is a rare genetic disease caused by mutation of the ABCG5/8 gene. Our aim was to elucidate the natural history and homeostasis of phytosterolemia.
We analyzed a Hutterite kindred ...consisting of 21 homozygotes with phytosterolemia assembled over a period of two decades, all of whom carried the ABCG8 S107X mutation and were treated with ezetimibe.
Most of these subjects were asymptomatic and devoid of clinical stigmata, and this, since they were ascertained primarily by a process of cascade testing, suggests that, relative to its true prevalence, phytosterolemia is a condition of low morbidity. All subjects have responded well to treatment with ezetimibe. Initial (pre-treatment) and post-ezetimibe levels of cholesterol and sitosterol were measured and percentage changes on ezetimibe were calculated. We found initial levels to be inversely related to subjects' ages as were percentage responses to ezetimibe therapy. There was also a direct correlation between initial levels and percentage responses to ezetimibe. Hence on-treatment levels were very uniform.
This evidence of a link with age leads us to propose that an age-related change in cholesterol and sterol homeostasis occurs at puberty in phytosterolemia and that the change is due to high sterol and/or stanol levels causing feedback inhibition of sterol regulatory element-binding protein (SREBP-2) processing. This would explain the well-documented phenomenon of depressed cholesterol synthesis in phytosterolemia. It is also well-known that LDL-receptor activity is increased, and this feasibly explains reduced LDL levels and consequent reduction of plasma cholesterol and sitosterol levels. Downregulated SREBP-2 processing would be expected to also lower proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and this would explain high LDL-receptor activity. The above state could be termed disrupted homeostasis and the alternative, seen mostly in children and characterized by hypercholesterolemia and hypersterolemia, simple homeostasis.
Background: Ursodeoxycholic acid (UDCA) treatment is associated with a reduced incidence of colonic neoplasia in preclinical models and in patients with conditions associated with an increased risk ...for colon cancer. We conducted a phase III, double-blind placebo-controlled trial of UDCA to evaluate its ability to prevent colorectal adenoma recurrence. Methods: We randomly assigned 1285 individuals who had undergone removal of a colorectal adenoma within the past 6 months to daily treatment with UDCA (8–10 mg/kg of body weight; 661 participants) or with placebo (624 participants) for 3 years or until follow-up colonoscopy. Recurrence rates (number of recurrent adenomas per unit time) were compared by use of a Huber–White variance estimator. Proportions of participants with one or more recurrent adenomas were compared with a Pearson chi-square statistic; adjusted odds ratios (ORs) were obtained by logistic regression. All statistical tests were two-sided. Results: We observed a non–statistically significant 12% reduction in the adenoma recurrence rate associated with UDCA treatment, compared with placebo treatment. However, UDCA treatment was associated with a statistically significant reduction (P = .03) in the recurrence of adenomas with high-grade dysplasia (adjusted OR = 0.61, 95% confidence interval = 0.39 to 0.96). We observed no statistically significant differences between UDCA and placebo groups in recurrence with regard to adenoma size, villous histology, or location. Conclusions: UDCA treatment was associated with a non–statistically significant reduction in total colorectal adenoma recurrence but with a statistically significant 39% reduction in recurrence of adenomas with high-grade dysplasia. Because severely dysplastic lesions have a high risk of progression to invasive colorectal carcinoma, this finding indicates that future chemoprevention trials of UDCA in individuals with such lesions should be considered.
The molecular mechanisms regulating the amount of dietary cholesterol retained in the body, as well as the body's ability to exclude selectively other dietary sterols, are poorly understood. An ...average western diet will contain about 250-500 mg of dietary cholesterol and about 200-400 mg of non-cholesterol sterols. About 50-60% of the dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. Thus, there exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. The major plant sterol species is sitosterol; hence the name of the disorder. Consequently, patients with this disease have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. We previously mapped the STSL locus to human chromosome 2p21 (ref. 4) and further localized it to a region of less than 2 cM bounded by markers D2S2294 and D2S2291 (M.-H.L. et al., manuscript submitted). We now report that a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated sitosterolemia patients.
It has been proposed that bile acid suppression of CYP7A1 gene expression is mediated through a gut-liver signaling pathway fibroblast growth factor (FGF)15/19-fibroblast growth factor receptor 4 ...which is initiated by activation of farnesoid X receptor in the ileum but not in the liver. This study evaluated whether FGF15/19 protein levels in the portal blood reflected changes in FGF15/19 mRNA in the ileum. Studies were conducted in Sprague Dawley rats and New Zealand white rabbits fed regular chow (controls), supplemented with cholesterol (Ch) or cholic acid (CA). After feeding CA, ileal FGF15 mRNA increased 8.5-fold in rats and FGF19 rose 16-fold in rabbits associated with 62 and 75% reduction of CYP7A1 mRNA, respectively. Neither FGF15 nor FGF19 protein levels changed in the portal blood to correspond with the marked increase of FGF15/19 mRNA levels in the ileum or inhibited CYP7A1 expression in the liver. Further, in Ch-fed rats, CYP7A1 mRNA increased 1.9-fold (P < 0.001) although FGF15 mRNA levels in the ileum and portal blood FGF15 protein levels were not decreased. In Ch-fed rabbits, although FGF19 mRNA levels in the ileum and liver did not increase significantly, CYP7A1 mRNA declined 49% (P < 0.05). We were unable to find corresponding changes of FGF15/19 protein levels in the portal blood in rats and rabbits where the mRNA levels of FGF15/19 in the ileum and CYP7A1 in the liver change significantly.
Sitosterolemia is a rare, recessively inherited disorder characterized by increased absorption and delayed removal of noncholesterol sterols, which is associated with accelerated atherosclerosis, ...premature coronary artery disease, hemolysis, and xanthomatosis. Treatments include low-sterol diet and bile salt-binding resins; however, these often do not reduce the xanthomatosis. We examined the effects of the intestinal cholesterol/phytosterol transporter inhibitor ezetimibe added to cholestyramine in a young female patient with sitosterolemia and associated xanthomatosis. The patient was an 11-year-old female with sitosterolemia presenting with prominent xanthomas in the subcutaneous tissue of both elbows who was receiving treatment with cholestyramine 2 g once daily. Bilateral carotid bruits were audible, and a grade II/VI systolic murmur was detected at the left upper sternal border. She also had a low platelet count of 111,000/μL. Ezetimibe 10 mg once daily was added to the patient’s ongoing cholestyramine regimen, and she was evaluated for 1 year. The patient followed an unrestricted diet during the 1-year treatment period. After 1 year of treatment with ezetimibe added to ongoing cholestyramine therapy, the patient’s plasma sitosterol and campesterol levels decreased by approximately 50%. Her carotid bruits completely resolved, her systolic murmur diminished, and her platelet count rose to 268,000/μL. More remarkably, the tuberous xanthomas on her elbows had completely regressed. Ezetimibe added to ongoing low-dose cholestyramine therapy led to a marked improvement in plasma sterol concentrations, complete regression of xanthomatosis, resolution of carotid bruits, and improvement in cardiac murmur in a young female patient with sitosterolemia.
Mutations in either of two genes comprising the STSL locus, ATP-binding cassette (ABC)-transporters ABCG5 (encoding sterolin-1) and ABCG8 (encoding sterolin-2), result in sitosterolemia, a rare ...autosomal recessive disorder of sterol trafficking characterized by increased plasma plant sterol levels. Based upon the genetics of sitosterolemia, ABCG5/sterolin-1 and ABCG8/sterolin-2 are hypothesized to function as obligate heterodimers. No phenotypic difference has yet been described in humans with complete defects in either ABCG5 or ABCG8. These proteins, based upon the defects in humans, are responsible for regulating dietary sterol entry and biliary sterol secretion.
In order to mimic the human disease, we created, by a targeted disruption, a mouse model of sitosterolemia resulting in Abcg8/sterolin-2 deficiency alone. Homozygous knockout mice are viable and exhibit sitosterolemia.
Mice deficient in Abcg8 have significantly increased plasma and tissue plant sterol levels (sitosterol and campesterol) consistent with sitosterolemia. Interestingly, Abcg5/sterolin-1 was expressed in both liver and intestine in Abcg8/sterolin-2 deficient mice and continued to show an apical expression. Remarkably, Abcg8 deficient mice had an impaired ability to secrete cholesterol into bile, but still maintained the ability to secrete sitosterol. We also report an intermediate phenotype in the heterozygous Abcg8+/- mice that are not sitosterolemic, but have a decreased level of biliary sterol secretion relative to wild-type mice.
These data indicate that Abcg8/sterolin-2 is necessary for biliary sterol secretion and that loss of Abcg8/sterolin-2 has a more profound effect upon biliary cholesterol secretion than sitosterol. Since biliary sitosterol secretion is preserved, although not elevated in the sitosterolemic mice, this observation suggests that mechanisms other than by Abcg8/sterolin-2 may be responsible for its secretion into bile.
The nuclear receptor PXR (pregnane X receptor) is a broad-specificity sensor that recognizes a wide variety of synthetic drugs and xenobiotic agents. On activation by these compounds, PXR ...coordinately induces a network of transporters, cytochrome P450 enzymes, and other genes that effectively clear xenobiotics from the liver and intestine. Like PXR, the majority of its target genes also possess a broad specificity for exogenous compounds. Thus, PXR is both a sensor and effector in a well integrated and generalized pathway for chemical immunity. Although it is clear that PXR responds to numerous foreign compounds, it is unclear whether it possesses an endogenous ligand. To address this issue, we noted that there is substantial overlap in the substrate specificities of PXR and its critical CYP3A target gene. This prompted us to ask whether endogenous CYP3A substrates also serve as PXR ligands. We demonstrate that 5β-cholestane-3α,7α,12α-triol (triol), a cholesterol-derived CYP3A substrate, is a potent PXR agonist that effectively induces cyp3a expression in mice. This defines a critical salvage pathway that can be autoinduced to minimize triol accumulation. In contrast, triol can accumulate to very high levels in humans, and unlike mice, these people develop the severe clinical manifestations of cerebrotendinous xanthomatosis. The reason for these dramatic species differences has remained unclear. We now demonstrate that triol fails to activate human PXR or induce the CYPSA-salvage pathway. This explains why humans are more susceptible to sterol accumulation and suggests that synthetic ligands for human PXR could be used to treat cerebrotendinous xanthomatosis and other disorders of cholesterol excess.
PDF
