Increased bile lithogenicity by SCP2 via HMGCR and CYP7A1 regulation in human hepatocytes

Y, Cui; Li, Zhong‐Lian; Zhao, Erpeng; Zhang, Ju; Cui, Naiqiang

doi:10.4318/tjg.2013.0528

Cited by 4 publications

(1 citation statement)

References 24 publications

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“…We found that levels of CYP7A1 were increased in patient fibroblasts compared to control cells, which is in line with a previous report citing CYP7A1 repression in SCP2 -overexpressing human hepatocytes (Fig. 3 C) [ 21 ].…”

Section: Resultssupporting

confidence: 93%

SCP2 variant is associated with alterations in lipid metabolism, brainstem neurodegeneration, and testicular defects

2022

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Background The detoxification of very long-chain and branched-chain fatty acids and the metabolism of cholesterol to form bile acids occur largely through a process called peroxisomal β-oxidation. Mutations in several peroxisomal proteins involved in β-oxidation have been reported, resulting in diseases characterized by neurological defects. The final step of the peroxisomal β-oxidation pathway is catalyzed by sterol carrier protein-x (SCPx), which is encoded by the SCP2 gene. Previously, there have been two reports of SCPx deficiency, which resulted from a homozygous or compound heterozygous SCP2 mutation. We report herein the first patient with a heterozygous SCP2 mutation leading to SCPx deficiency. Results Clinical presentations of the patient included progressive brainstem neurodegeneration, cardiac dysrhythmia, muscle wasting, and azoospermia. Plasma fatty acid analysis revealed abnormal values of medium-, long-, and very long-chain fatty acids. Protein expression of SCPx and other enzymes involved in β-oxidation were altered between patient and normal fibroblasts. RNA sequencing and lipidomic analyses identified metabolic pathways that were altered between patient and normal fibroblasts including PPAR signaling, serotonergic signaling, steroid biosynthesis, and fatty acid degradation. Treatment with fenofibrate or 4-hydroxytamoxifen increased SCPx levels, and certain fatty acid levels in patient fibroblasts. Conclusions These findings suggest that the patient’s SCP2 mutation resulted in decreased protein levels of SCPx, which may be associated with many metabolic pathways. Increasing SCPx levels through pharmacological interventions may reverse some effects of SCPx deficiency. Collectively, this work provides insight into many of the clinical consequences of SCPx deficiency and provides evidence for potential treatment strategies.

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Section: Resultssupporting

confidence: 93%