Contact Details:

c.shoulders@qmul.ac.uk

Carol Shoulders graduated from the Open University in 1981 whilst working at the Medical Research Council’s Laboratory of Molecular Biology in Cambridge and was awarded a DPhil by Oxford University in 1984 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 an expert panel member for the Finnish Academy Research Council for Health, 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.

Current research interests

The group’s current research is focussed on identifying the diverse range of cellular processes that contribute to premature cardiovascular disease through promoting the assembly and secretion of very low density lipoproteins (VLDL) and chylomicrons (Cm). Our approach involves identifying the major genes underlying the pernicious, highly atherogenic FCHL-lipid abnormalities and characterising the key proteins of the COP (coat protein) transport machinery involved in initiating the intracellular transport of Cm and VLDL. Our principal experimental approaches include high-through-put genotyping, statistical analyses, bioinformatics, FISH, genome-wide gene expression analyses, cell and structural biology plus biochemistry.

1. Elucidating the Genetics and the Underlying Biology of FCHL-lipid Abnormalities. From genetic and gene expression studies it is apparent that hitherto unsuspected cellular pathways contribute to both cell and whole-body lipid homeostasis, and that the genetic complexity of FCHL is undoubtedly rooted in the diversity of the intra- and inter-cellular processes of the various organs that handle a wide range of lipid species. Our results from the largest genome-wide linkage scan ever performed in FCHL, plus a cohort of ~300 extended FCHL families and of population controls provide us with an excellent springboard to establish the genetic causes of FCHL, plus the cellular systems perturbed in this condition, and seemingly unrelated genetic disorders.
   
   
2. Establishing Roles of Sar1 Isoforms in Lipid Homeostastis. Newly synthesised proteins and lipid-protein complexes leave the endoplasmic reticulum in COPII transport vehicles assembled from membrane lipids, plus Sar1, Sec23/24 and Sec13/31. We are using genome-wide gene expression and biochemical analyses to dissect out the individual and overlapping functions of Sar1a and Sar1b in the intracellular transport of newly assembled, apoB-containing lipoproteins. These data are providing important insights into the aetiology of both perturbed cellular and serum lipid levels in patients with Chylomicron Retention Disorder, caused by mutations of Sar1b.
   
   
3. Homing in on the Biochemical Properties of a Highly Conserved, Ancient, DUF (Domain of Unknown Function) Protein. Through multiple approaches (gene expression, metabolomic, structural biology and biochemistry) we have established that this DUF protein contributes to the synthesis of cholesterol and triglyceride, and pin-pointed the probable biochemical reaction involved. Important future studies include establishing the role of DUF in certain kidney and brain cell types and its contribution to the Metabolic Syndrome.
   

Key publications

• Horswell DS, Ringham HE, Shoulders CC “New technologies for delineating and characterizing the lipid exome: prospects for understanding familial combined hyperlipidemia”. J Lipid Res., 49, (2009); S370-375.
  
  
• Shoulders CC. “The FTO (fat mass and obesity-gene) gene: big in adipocyte lipolysis?’’ J Lipid Res., 49, (2008); 495-496.
  
  
• Lelliott CJ, Ljungberg A, Ahnmark A, William-Olsson L, Ekroos K, Elmgren A, Arnerup G, Shoulders CC, Oscarsson J, Linden D. “Hepatic PGC-1over-expression in mice causes combined hyperlipidemia and a blunted response to PPAR activation’’. Arterioscler Thromb. Vasc. Biol., 27, (2007); 2707-13.
  
  
• Eichenbaum-Voline S, Olivier M, Jones EL, Naoumova RP, Jones B, Gau B, Patel HN, Seed M, Betteridge DJ, Galton DJ, Rubin EM, Scott J, Shoulders CC, Pennacchio LA, “Linkage and association between distinct variants of the APOA1/C3/A4/A5 gene cluster and familial combined hyperlipidemia”. Arterioscler Thromb. Vasc. Biol., 24, (2004)167-174.
  
  
• Naoumova RP, Bonney SA, Eichenbaum-Voline S, Patel HN, Jones B, Jones EL, Amey J, Colilla S, Neuwirth CKY, Seed M, Betteridge JD, Galton DJ, Cox NJ, Bell GI, Scott J, Shoulders CC. “Confirmed locus on chromosome 11 and candidate loci on 6q and 8p for the cholesterol and triglyceride traits of combined hyperlipidemia”. Arterioscler Thromb. Vas. Biol., 23, (2003); 2070-2077.
  
  
• Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, 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. “Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders”. Nature Genetics, 34, (2003); 29-31.
  
  
• Bradbury P, Mann CJ, Köchl S, Anderson TA, Chester SA, Hancock JM, Ritchie PJ, Amey J, Harrison G, Levitt DG, Banaszak LJ, Scott J, Shoulders CC. “A common binding site on the microsomal triglyceride transfer protein for apolipoprotein B and protein disulphide isomerase”. J Biol. Chem., 274, (1999); 3159-3164.
  
  
• Mann CJ, Anderson TA, Read J, Chester SA, Harrison GB, Kochl S, Ritchie PJ, Hussain FS, Bradbury P, Vanloo B, Rosseneu M, Infante R, Hancock JM, Levitt DG, Banaszak LJ, Scott J, Shoulders CC. “Vitellogenin provides the evolutionary and mechanistic basis for the assembly and secretion of atherogenic lipoproteins”. J Mol Biol., 285, (1999); 391-408.
  
  
• Shoulders CC, Narcisi TME, Read J, Chester SA, Brett DJ, Scott J, Anderson TA, Levitt DG, Banaszak LJ. “The abetalipoproteinemia gene is a member of the vitellogenin family and encodes an -helical domain”. Nature Struct. Biol., 1, (1994); 285-286.