Unravelling new pathways of sterol metabolism: lessons learned from in-born errors and cancer.

Yuqin Wang,William J Griffiths

doi:10.1097/mco.0000000000000442

Abstract

Purpose of reviewTo update researchers of recently discovered metabolites of cholesterol and of its precursors and to suggest relevant metabolic pathways.Recent findingsPatients suffering from inborn errors of sterol biosynthesis, transport and metabolism display unusual metabolic pathways, which may be major routes in the diseased state but minor in the healthy individual. Although quantitatively minor, these pathways may still be important in healthy individuals. Four inborn errors of metabolism, Smith-Lemli-Opitz syndrome, cerebrotendinous xanthomatosis and Niemann Pick disease types B (NPB) and C (NPC) result from mutations in different genes but can generate elevated levels of the same sterol metabolite, 7-oxocholesterol, in plasma. How this molecule is metabolized further is of great interest as its metabolites may have an important role in embryonic development. A second metabolite, abundant in NPC and NPB diseases, cholestane-3β,5α,6β-triol (3β,5α,6β-triol), has recently been shown to be metabolized to the corresponding bile acid, 3β,5α,6β-trihydroxycholanoic acid, providing a diagnostic marker in plasma. The origin of cholestane-3β,5α,6β-triol is likely to be 3β-hydroxycholestan-5,6-epoxide, which can alternatively be metabolized to the tumour suppressor dendrogenin A (DDA). In breast tumours, DDA levels are found to be decreased compared with normal tissues linking sterol metabolism to cancer.SummaryUnusual sterol metabolites and pathways may not only provide markers of disease, but also clues towards cause and treatment.

Highlights

In vertebrates, cholesterol can be synthesized by all cells from acetyl-CoA
Following cyclization of squalene to lanosterol via squalene-2,3-epoxide the pathway divides into two main routes known as the Bloch and Kandustch–Russell pathways leading to desmosterol and 7-dehydrocholesterol (7-DHC), respectively, as the immediate precursors of cholesterol [1]
We have found 7-OC to be elevated in cerebrotendinous xanthomatosis (CTX) plasma and speculate that this is a result of upregulation of CYP7A1, as consequence of reduced negative-feedback by primary bile acids and use of 7-DHC as the enzyme substrate [7,8] (Fig. 1)

Summary

Introduction

Cholesterol can be synthesized by all cells from acetyl-CoA. Following cyclization of squalene to lanosterol via squalene-2,3-epoxide the pathway divides into two main routes known as the Bloch and Kandustch–Russell pathways leading to desmosterol and 7-dehydrocholesterol (7-DHC), respectively, as the immediate precursors of cholesterol [1]. Four inborn errors of metabolism, Smith-Lemli-Opitz syndrome, cerebrotendinous xanthomatosis and Niemann Pick disease types B (NPB) and C (NPC) result from mutations in different genes but can generate elevated levels of the same sterol metabolite, 7-oxocholesterol, in plasma.

Results

Conclusion