Shoulders, Carol

Carol Shoulders

Professor of Lipidology

Carol Shoulders graduated from the Open University in 1980 whilst working at the Medical Research Council’s Laboratory of Molecular Biology in Cambridge and was awarded a DPhil by Oxford University in 1983 for cloning the human apolipoprotein A1 gene. Her subsequent activities within the lipid biology field include identifying that mutations of the microsomal triglyceride transfer protein gene cause the devastating condition, abetalipoproteinemia; and that the abetalipoproteinemia gene-product belongs to the gene family which encodes the egg yolk protein, vitellogenin, and apolipoprotein B, the obligatory protein component of the major lipid carrying particles in the circulation. She also led the group which discovered the cause of the rare disorder Chylomicron Retention Disorder, and established that newly assembled chylomicrons, despite their very large size, utilise the COPII vesicular transport system to navigate their journey through the complex intracellular transport system of enterocytes. Carol Shoulders joined the William Harvey Research Institute in 2009 to continue studies into the highly atherogenic, disorder Familial Combined Hyperlipidemia (FCHL) and to diversify into other areas of lipid biology, work begun at the MRC Clinical Sciences Centre, Imperial College London. Carol Shoulders is a committee member of the Heart-UK Research Board, a scientific advisor for the American Society of Biochemistry and Molecular Biology Today Journal and an Associate Editor for the Journal of Lipid Research.

Summary of Research

The group’s current research is focused on identifying the diverse range of cellular processes that contribute to whole-body lipid homeostasis Our approach involves identifying the causes of the pernicious, highly atherogenic disorder, Familial Combined Hyperlipidemia (FCHL); and characterizing the working relationships between the ER-localized machineries that synthesize cholesterol and the COPII vesicles, which transport multiple proteins and lipid complexes to the Golgi apparatus, en route to their final destinations. Our principal experimental approaches include genetic linkage analyses, high-through-put sequencing, statistical analyses, bioinformatics, genome-wide gene expression analyses, cell and structural biology plus biochemistry.

Elucidating the Genetics and the Underlying Biology of FCHL-lipid Abnormalities.
From our FCHL studies (see cartoon), it is apparent that the genetic complexity of FCHL is rooted in the diversity of the intra- and inter-cellular processes of the various organs (e.g. liver, adipose tissue (see Chan), adrenal gland (see Metherell) that handle diverse ranges of lipid species. Crucially, our findings have already opened the door for developing more personalised, efficacious, therapies for this common and highly atherogenic disorder, and promise to provide new mechanistic insights into both its pathogenesis, and that of some seemingly unrelated genetic disorders.

Lipoprotein Production, ER-cholesterol Synthesis and ER-transport Vesicle Assembly.
We are investigating the post-transcriptional mechanisms regulating ER-cholesterol synthesis (see cartoon), the rationale being that most nucleated cells synthesis cholesterol de novo (e.g. adrenal for steroid synthesis, Metherell and King); and >50% of circulating cholesterol derives from de novo synthesis. We envisage that further delineation of the apoB-lipoprotein/cholesterol/COPII machineries will provide important insights into the nature and causes of ER-stress in metabolic, cardiovascular and endocrine disease.

 

Members of the Group

Research staff: Dr C Hutchison

Wellcome Trust Clinical Training Fellow: Dr R Sivapackianathan

PhD Student: Ms Tozen Ozkan

Click here to download PFIDO.

 

Key Publications

For a full list of publist publications click here

Aikio M, Elamaa H, Vicente D, Izzi V, Kaur I, Seppinen L, Speedy HE, Kaminska D, Kuusisto S, Sormunen R, Heljasvaara R, Jones EL, Muilu M, Jauhiainen M, Pihlajamäki J, Savolainen MJ, Shoulders CC, Pihlajaniemi T. (2014). Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition. Proc Natl Acad Sci 111(30):E3043-52. 10.1073/pnas.1405879111

Fryer LG, Jones B, Duncan EJ, Hutchison CE, Ozkan T, Williams PA, Alder O, Nieuwdorp M, Townley AK, Mensenkamp AR, Stephens DJ, Dallinga-Thie GM, Shoulders CC. (2014). The Endoplasmic Reticulum Coat Protein II Transport Machinery Coordinates Cellular Lipid Secretion and Cholesterol Biosynthesis. J Biol Chem Vol. 289, 4244-4261. 10.1074/jbc.M113.479980
 
Salm MP, Horswell SD, Hutchison CE, Speedy HE, Yang X, Liang L, Schadt EE, Cookson WO, Wierzbicki AS, Naoumova RP, Shoulders CC. (2012). The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism. Genome Res Vol.22, (6) 1144-1153. 10.1101/gr.126037.111

Calandra S, Tarugi P, Speedy HE, Dean AF, Bertolini S, Shoulders CC. (2011). Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk. J LIPID RES Vol.52, (11) 0022-2275 1885-1926. 10.1194/jlr.R017855

Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, Eichenbaum-Voline S, Rudling M, Myrdal U, Annesi G, Naik S, Meadows N, Quattrone A, Islam SA, Naoumova RP, Angelin B, Infante R, Levy E, Roy CC, Freemont PS, Scott J, Shoulders CC. (2003). Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. NAT GENET Vol.34, (1) 1061-4036 29-31. 10.1038/ng1145

Mann CJ, Anderson TA, Read J, Chester SA, Harrison GB, Köchl S, Ritchie PJ, Bradbury P, Hussain FS, Amey J, Vanloo B, Rosseneu M, Infante R, Hancock JM, Levitt DG, Banaszak LJ, Scott J, Shoulders CC. (1999). The structure of vitellogenin provides a molecular model for the assembly and secretion of atherogenic lipoproteins. J Mol Biol Vol.285, (1) 0022-2836 391-408. 10.1006/jmbi.1998.2298

Baralle FE, Shoulders CC, Proudfoot NJ. (1980). The primary structure of the human ε-globin gene. Cell Vol.21, (3) 621-626. 10.1016/0092-8674(80)90425-0
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