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Cholic acid for primary bile acid synthesis defects: a life-saving therapy allowing a favorable outcome in adulthood.

ABSTRACT: BACKGROUND:Oral cholic acid (CA) replacement has been shown to be an effective therapy in children with primary bile acid synthesis defects, which are rare and severe genetic liver diseases. To date there has been no report of the effects of this therapy in children reaching adulthood. The aim of the study was to evaluate the long-term effectiveness and safety of CA therapy. METHODS:Fifteen patients with either 3?-hydroxy-?5-C27-steroid oxidoreductase (3?-HSD) (n?=?13) or ?4-3-oxosteroid 5?-reductase (?4-3-oxo-R) (n?=?2) deficiency confirmed by mass spectrometry and gene sequencing received oral CA and were followed prospectively. RESULTS:The median age at last follow-up and the median time of follow-up with treatment were 24.3 years (range: 15.3-37.2) and 21.4 years (range: 14.6-24.1), respectively. At last evaluation, physical examination findings and blood laboratory test results were normal in all patients. Liver sonograms were normal in most patients. Mean daily CA dose was 6.9 mg/kg of body weight. Mass spectrometry analysis of urine showed that excretion of the atypical metabolites remained low or traces in amount with CA therapy. Liver fibrosis scored in liver biopsies or assessed by elastography in 14 patients, after 10 to 24 years with CA therapy, showed a marked improvement with disappearance of cirrhosis (median score?

SUBMITTER: Gonzales E

PROVIDER: S-EPMC6206929 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Cholic acid for primary bile acid synthesis defects: a life-saving therapy allowing a favorable outcome in adulthood.

Gonzales Emmanuel E Matarazzo Lorenza L Franchi-Abella Stéphanie S Dabadie Alain A Cohen Joseph J Habes Dalila D Hillaire Sophie S Guettier Catherine C Taburet Anne-Marie AM Myara Anne A Jacquemin Emmanuel E

Orphanet journal of rare diseases 20181029 1

<h4>Background</h4>Oral cholic acid (CA) replacement has been shown to be an effective therapy in children with primary bile acid synthesis defects, which are rare and severe genetic liver diseases. To date there has been no report of the effects of this therapy in children reaching adulthood. The aim of the study was to evaluate the long-term effectiveness and safety of CA therapy.<h4>Methods</h4>Fifteen patients with either 3β-hydroxy-Δ<sup>5</sup>-C<sub>27</sub>-steroid oxidoreductase (3β-HSD ...[more]

PMID: 30373615

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Project description:Background & aimsAlthough fat loss is observed in patients with cholestasis, how chronically elevated bile acids (BAs) impact white and brown fat depots remains obscure.MethodsTo determine the direct effect of pathological levels of BAs on lipid accumulation and mitochondrial function, primary white and brown adipocyte cultures along with fat depots from two separate mouse models of cholestatic liver diseases, namely (i) genetic deletion of farnesoid X receptor (Fxr); small heterodimer (Shp) double knockout (DKO) and (ii) injury by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), were used.ResultsAs expected, cholestatic mice accumulate high systemic BA levels and exhibit fat loss. Here, we demonstrate that chronic exposure to pathological BA levels results in mitochondrial dysfunction and defective thermogenesis. Consistently, both DKO and DDC-fed mice exhibit lower body temperature. Importantly, thermoneutral (30 °C) housing of the cholestatic DKO mice rescues the decrease in brown fat mass, and the expression of genes responsible for lipogenesis and regulation of mitochondrial function. To overcome systemic effects, primary adipocyte cultures were treated with pathological BA concentrations. Mitochondrial permeability and respiration analysis revealed that BA overload is sufficient to reduce mitochondrial function in primary adipocytes, which is not as a result of cytotoxicity. Instead, we found robust reductions in uncoupling protein 1 (Ucp1), PR domain containing 16 (Prdm16), and deiodinase, iodothyronine, type II (Dio2) transcripts in brown adipocytes upon treatment with chenodeoxycholic acid, whereas taurocholic acid led to the suppression of Dio2 transcript. This BA-mediated decrease in transcripts was alleviated by pharmacological activation of UCP1.ConclusionsHigh concentrations of BAs cause defective thermogenesis by reducing the expression of crucial regulators of mitochondrial function, including UCP1, which may explain the clinical features of hypothermia and fat loss observed in patients with cholestatic liver diseases.Impact and implicationsWe uncover a detrimental effect of chronic bile acid overload on adipose mitochondrial function. Pathological concentration of different BAs reduces the expression of distinct genes involved in energy expenditure, which can be mitigated with pharmacological UCP1 activation.

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Cholic acid for primary bile acid synthesis defects: a life-saving therapy allowing a favorable outcome in adulthood.

Publications

Cholic acid for primary bile acid synthesis defects: a life-saving therapy allowing a favorable outcome in adulthood.

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