ORCID Profile
0000-0002-0902-0062
Current Organisation
UNSW Sydney
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Annual Reviews
Date: 06-01-2016
DOI: 10.1146/ANNUREV-PHARMTOX-010715-103233
Abstract: Oxysterols have long been known for their important role in cholesterol homeostasis, where they are involved in both transcriptional and posttranscriptional mechanisms for controlling cholesterol levels. However, they are increasingly associated with a wide variety of other, sometimes surprising cell functions. They are activators of the Hedgehog pathway (important in embryogenesis), and they act as ligands for a growing list of receptors, including some that are of importance to the immune system. Oxysterols have also been implicated in several diseases such as neurodegenerative diseases and atherosclerosis. Here, we explore the latest research into the roles oxy-sterols play in different areas, and we evaluate the current evidence for these roles. In addition, we outline critical concepts to consider when investigating the roles of oxysterols in various situations, which includes ensuring that the concentration and form of the oxysterol are relevant in that context—a caveat with which many studies have struggled.
Publisher: Portland Press Ltd.
Date: 31-01-2020
DOI: 10.1042/BCJ20190647
Abstract: Cholesterol synthesis is a tightly controlled pathway, with over 20 enzymes involved. Each of these enzymes can be distinctly regulated, helping to fine-tune the production of cholesterol and its functional intermediates. Several enzymes are degraded in response to increased sterol levels, whilst others remain stable. We hypothesised that an enzyme at a key branch point in the pathway, lanosterol 14α-demethylase (LDM) may be post-translationally regulated. Here, we show that the preceding enzyme, lanosterol synthase is stable, whilst LDM is rapidly degraded. Surprisingly, this degradation is not triggered by sterols. However, the E3 ubiquitin ligase membrane-associated ring-CH-type finger 6 (MARCH6), known to control earlier rate-limiting steps in cholesterol synthesis, also control levels of LDM and the terminal cholesterol synthesis enzyme, 24-dehydrocholesterol reductase. Our work highlights MARCH6 as the first ex le of an E3 ubiquitin ligase that targets multiple steps in a biochemical pathway and indicates new facets in the control of cholesterol synthesis.
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.JLR.2022.100295
Abstract: The enzymatic pathway of cholesterol biosynthesis has been well characterized. However, there remain several potential interacting proteins that may play ancillary roles in the regulation of cholesterol production. Here we identified ERG28 (C14orf1), a homologue of the yeast protein Erg28p, as a player in mammalian cholesterol synthesis. ERG28 is conserved from yeast to humans, but has been largely overlooked in mammals. Using qRT-PCR, luciferase assays, and publicly available ChIP-seq data, we found that transcription of this gene is driven by the transcription factor SREBP-2, akin to the vast majority of cholesterol synthesis enzymes, as well as identifying sterol responsive elements and co-factor binding sites in its proximal promoter. Based on a split luciferase system, ERG28 interacted with itself and two enzymes of cholesterol synthesis (NSDHL and SC4MOL). Huh7 ERG28-knockout cell-lines were generated, revealing reduced total cholesterol levels in sterol-depleted environments. Additionally, radiolabeled metabolic flux assays showed a 60 to 75% reduction in the rate of cholesterol synthesis in the knockout versus wild-type cells, which could be rescued by expression of ectopic ERG28. Unexpectedly, knockout of ERG28 also impaired the activation of SREBP-2 under sterol replete conditions, by a yet-to-be defined mechanism. These results indicate that ERG28 is clearly involved in cholesterol synthesis, although the precise role this non-catalytic protein plays in this complex metabolic pathway remains to be fully elucidated. A deeper understanding of ERG28, and other ancillary proteins of cholesterol synthesis, may help inform therapeutic strategies for diseases associated with aberrant cholesterol metabolism.
Publisher: Elsevier BV
Date: 02-2020
Publisher: Elsevier BV
Date: 08-2020
Publisher: Elsevier BV
Date: 2021
No related grants have been discovered for Isabelle M Capell-Hattam.