Dataset Information

Pathological bile acid concentrations in chronic cholestasis cause adipose mitochondrial defects.

ABSTRACT:

Background & aims

Although fat loss is observed in patients with cholestasis, how chronically elevated bile acids (BAs) impact white and brown fat depots remains obscure.

Methods

To 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.

Results

As 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.

Conclusions

High 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 implications

We 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.

SUBMITTER: Zhou W

PROVIDER: S-EPMC10133756 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

Pathological bile acid concentrations in chronic cholestasis cause adipose mitochondrial defects.

Zhou Weinan W VanDuyne Philip P Zhang Chi C Liu Yushan Y Riessen Ryan R Barragan Maribel M Rowitz Blair M BM Teran-Garcia Margarita M Boppart Stephen A SA Anakk Sayeepriyadarshini S

JHEP reports : innovation in hepatology 20230223 5

<h4>Background & aims</h4>Although fat loss is observed in patients with cholestasis, how chronically elevated bile acids (BAs) impact white and brown fat depots remains obscure.<h4>Methods</h4>To 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 (<i>Fxr</i>); sm ...[more]

PMID: 37122689

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Dataset Information

Pathological bile acid concentrations in chronic cholestasis cause adipose mitochondrial defects.

Background & aims

Methods

Results

Conclusions

Impact and implications

Publications

Pathological bile acid concentrations in chronic cholestasis cause adipose mitochondrial defects.

Similar Datasets

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