Lipids and the Metabolic Syndrome
Richard Henderson
rmh1003@cam.ac.uk
Essays
Key themes: how plasma HDL and LDL levels are controlled and influenced by drugs, LXR
and PPAR as therapeutic targets, reverse cholesterol transport, contribution of Brown and
Goldstein
2018 (Paper 4) Describe the mechanisms controlling plasma HDL and LDL levels and how
these are influenced by drugs.
2017 (Paper 3) How may drugs target cellular processes to control plasma LDL levels?
2015 (Paper 3) Discuss liver X receptors and peroxisome proliferator-activated receptors as
therapeutic targets.
2014 (Paper 3) Write an essay on the mechanism of reverse cholesterol transport. How
does it help in lipid homeostasis and is it a valid therapeutic target?
2013 (Paper 3) Summarise, with appropriate examples, the contributions that M.S.
Brown and J.L. Goldstein have made to our understanding of the function and expression of
the LDL receptor.
2013 (Paper 4) Explain why liver X receptors (LXRs) and peroxisome proliferator-activated
receptors (PPARs) are considered important targets in developing therapeutic strategies
against the metabolic syndrome.
2012 (Paper 4) Write on mechanisms influencing reverse cholesterol transport and
drugs that may influence them.
2009 (Paper 4) Write an essay on the mechanisms that lead to changes in plasma LDL levels.
How may drugs influence these mechanisms?
2008 (Paper 3) Write an essay on the mechanism of reverse cholesterol transport and how
it may be targeted by drugs now and in the future.
2008 (Paper 4) Where would the field of lipid therapy be if M.S. Brown and J.L. Goldstein
had chosen to work in a different field?
2006 (Paper 4) Write an essay on the cellular mechanisms involved in the regulation of
cellular sterols and blood lipids.
Bibliography:
Key references marked *
The LDL receptor/familial hypercholesterolaemia story
*Goldstein J.L., Brown, M.S., Anderson, R.G.W., Russell, D.W. & Schneider, W.J. Receptor-
mediated endocytosis - concepts emerging from the LDL receptor system. Annual Review of
Cell Biology 1:1-39, 1985.
Bilheimer, D.W., Goldstein, J.L., Grundy, S.M., Starzl, T.E. & Brown, M.S. (1984). Liver-
transplantation to provide low-density-lipoprotein receptors and lower plasma-cholesterol
,in a child with homozygous familial hypercholesterolemia. New England Journal of Medicine
311, 1658-1664
Mahley, R.W. (1988) Apolipoprotein E: Cholesterol transport protein with expanding role in
biology. Science, 240, 622-629.
Plump, A.S., Smith, J.D., Hayek, T., Aalto-Setala, K., Walsh, A., Verstuyft, J.G., Rubin, E.M. &
Breslow, J.L. (1992) Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-
deficient mice created by homologous recombination in ES cells. Cell, 71, 343-353.
*Nair P (2013). Brown and Goldstein: the cholesterol chronicles. Proc Natl Acad Sci U S A
110, 14829-14832.
Gene therapy
Herz, J. & Gerard, R.D. (1993) Adenovirus-mediated transfer of low density lipoprotein
receptor gene acutely accelerates cholesterol clearance in normal mice. Proceedings of the
National Academy of Sciences of the United States of America, 90, 2812-2816.
Pages, J.C., Andreoletti, M., Bennoun, M., Vons, C., Elcheroth, J., Lehn, P., Houssin, D.,
Chapman, J., Briand, P., Benarous, R., Franco, D. & Weber, A. (1995) Efficient retroviral-
mediated gene transfer into primary culture of murine and human hepatocytes: Expression
of the LDL receptor. Human Gene Therapy, 6, 21-30.
Raper, S.E., Grossman, M., Rader, D.J., Thoene, J.G., Clark, B.J. III, Kolansky, D.M., Muller,
D.W.M. & Wilson, J.M. (1996) Safety and feasibility of liver-directed ex vivo gene therapy for
homozygous familial hypercholesterolemia. Annals of Surgery, 223, 116-126.
Zhang, S.H., Reddick, R.L., Piedrahita, J.A. & Maeda, N. (1992) Spontaneous
hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science, 258,
468-471.
PCSK9
*Preiss D. & Mafham M. (2017). PCSK9 inhibition: the dawn of a new age in cholesterol
lowering? Diabetologia 60, 381-389.
*Horton J.D., Cohen J.C., & Hobbs H.H. (2007). Molecular biology of PCSK9: its role in LDL
metabolism. Trends Biochem Sci 32, 71-77.
*Lagace T.A., Curtis D.E., Garuti R. et al. (2006). Secreted PCSK9 decreases the number of
LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest 116, 2995-3005.
Abifadel M., Varret M., Rabes J.P. et al. (2003). Mutations in PCSK9 cause autosomal
dominant hypercholesterolemia. Nat Genet 34, 154-156.
SREBP/SCAP
,*Brown, M. S. & Goldstein, J. L. (1999). A proteolytic pathway that controls the cholesterol
content of membranes, cells, and blood. Proc Natl Acad Sci U S A 96, 11041-11048.
*Grand-Perret, T., Bouillot, A., Perrot, A., Commans, S., Walker, M., & Issandou, M. (2001).
SCAP ligands are potent new lipid-lowering drugs. Nature Medicine 7, 1332-1338.
Korn, B. S., Shimomura, I., Bashmakov, Y., Hammer, R. E., Horton, J. D., Goldstein, J. L., &
Brown, M. S. (1998). Blunted feedback suppression of SREBP processing by dietary
cholesterol in transgenic mice expressing sterol-resistant SCAP(D443N). J Clin Invest 102,
2050-2060.
T. Yang, J. L. Goldstein, and M. S. Brown. Overexpression of membrane domain of SCAP
prevents sterols from inhibiting SCAP.SREBP exit from endoplasmic reticulum. J.Biol.Chem.
275 (38):29881-29886, 2000.
*Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL, & Brown MS
(2002). Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1,
a membrane protein that facilitates retention of SREBPs in ER. Cell 110, 489-500.
*Repa JJ & Mangelsdorf DJ (2002). The liver X receptor gene team: Potential new players in
atherosclerosis. Nat Med 8, 1243-1248.
Joseph SB et al. (2002). Synthetic LXR ligand inhibits the development of atherosclerosis in
mice. Proc Natl Acad Sci USA 99, 7604-7609.
Tangirala RK et al. (2002). Identification of macrophage liver X receptors as inhibitors of
atherosclerosis. Proc Natl Acad Sci USA 99, 11896-11901.
, Lecture 1:
Desensitisation of receptors
- Most extensively studied with regard to the beta2 adrenoceptor
- Uncoupling of the receptor from Gs (takes place over seconds to minutes)
- Sequestration of the receptor (over minutes)
- Down-regulation by degradation of the receptors in lysosomes (minutes to hours)
- These processes are mediated by homologous and heterologous desensitisation.
- Homologous and heterologous desensitisation involve phosphorylation of the
receptors by two different protein kinases.
- The process of sequestration of the beta2 adrenoceptor is poorly understood.
- Sequestration has been extensively studied with regard to the Low Density
Lipoprotein (LDL) receptor
- Many of the mechanisms involved are common to many membrane proteins and so
this provides a model for receptor regulation in general
- Study of the LDL receptor was prompted by interest in familial
hypercholesterolaemia (FH), described in early 1960s with more than 1,200 distinct
mutations identified.
Diabetes and Cardiovascular Events
- Diabetes leads to an elevated risk of cardiovascular related conditions, including
angina, myocardial infarction, heart failure, stroke.
- The incidence of cardiovascular disease is not evenly distributed across the UK,
notably prevalent in central Scotland, west Midlands, south Wales and central
London. The lifestyle is less important than genetics.
- There are also other medical conditions related to diabetes: retinopathy (leading
cause of sight loss in people of working age in England and Wales), gangrene and
limb amputation (up to 100 people a week have a limb amputated in the UK as a
result of diabetes), depression (twice as high among people with type 2 diabetes
than in those without the condition).
- In England and Wales, diabetes is a major cause of mortality with over 23,300
additional deaths in 2010-2011.
Diabetes and Obesity
- Obesity and overweight are major risk factors for type 2 diabetes.
- The association between age and diabetes becomes weaker.
- Both obesity and type 2 diabetes are strongly associated with unhealthy diets and
physical inactivity.
- People from black, Asian and other minority ethnic groups are at an equivalent risk
of type 2 diabetes at lower BMI levels than white European population.
- Deprivation is closely linked to the risk of type 2 diabetes, related to diet.
Metabolic Syndrome
- Abdominal obesity
- High plasma triglycerides
- Low HDL cholesterol and high LDL cholesterol
