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Cholesterol & T2Diab

Berger et al 2005 Review: PPARs. 3 isoforms alpha, beta(/delta), and gamma. Oblgiate dimers with RXR receptors. Agonist decr circulating FFAs and incr conc in adipose tissue (protects liver).PPARa KO mice have hepatic steatosis, hyperlipiaemia and hypoglycaemia.
Kubota et al 1999 Heterozyg PPARy KO have reduced adiposity, causes mild lipodystrophy and reduced weight gain (less intake, ^ spend) + incr insulin sensitivity on high fat diet (vs controls), liver somewhat protected from fat too. Homozyg is E lethal, dodgy placenta.
He et al 2003 PPARy KO tied to aP2 expression (hoped to incr adipocyte number before shut down to avoid disrupting development). Fat cells still died, drew conclusions about PPARy without considering the stress placed on surviving fat cells, Kubota 1999 -same issues?
Mayerson et al 2002 Human study: 3 months of rosiglitazone caused fat redistribution from visceral to subcutaneous (less bad for liver, no portal drainage). Measured by MRI (visceral) and X-ray absorption (subcut). Improved insulin sensitivity
Combs et al 2002 PPARy agonists (2 week treatment) increase adiponectin (in mice and humans) which in turn seems to cause insulin sensitisation. Reduced blood glucose in mice. Quantitative western blotting used for adiponectin increase.
Li et al 2000 PPARy agonists shown to inhibit atherosclerosis in male LDLR KO mice fed a western diet. Female mice didnt benefit, also had incr expression of LDL not seen in males. Differences likely hormonal, prelim results showed ovariectomy removed gender difference
Chen et al 2001 PPARy agonist inhibited atherosclerosis in ApoE KO mice. Only used males. Saw an increase in HDL. Very similar to Li 2000.
Minamikawa et al 1998 Shows inhibition of plaque progression in humans treated with thiazolidinediones (PPARy agonists). Used ultrasound to measure. Study of both men and women, didnt analyse for gender differences. 6 months treatment.
Goya et al 2004 PPARa agonists (but not PPARy) incr NO production in vascular cells, used fenofibrate as PPARa agonist. Assayed for radiolabelled L-citrulline. Agonists increased activity (experiments in cell lysates) and expression (experiments in intact cells) of eNOS.
Minoura et al 2004 Describes a PPARy partial agonist, may be safer than full agonists. Used at lower doses than most PPARy full agonists (excluding rosiglitazone) and has a smaller maximum response as less toxic than rosi. Have been trialled, not sure if they still are?
Van Wijk et al 2003 Meta-analysis showing that different thiazolidinediones do not have the same effects. Despite efficacy in reducing glycaemia they have varying effectiveness on improving lipid profile.
Hegarty et al 2004 Non-selective PPAR agonists (acting preferentially at a and y isoforms) have been extensively trialled and have shown benefits in improving lipid profile. Also sensitises to insulin, possibly by reducing lipotoxicity.
Brown and Goldstein 1999 Review: S1P = serine protease, cleaves loop of SREBP in ER lumen. S2P = zinc metalloproteinase cleaving 3 residues into the membrane. SREBP N termini are basic-loop-helix leucine zipper transcription factors. N terminus recruits coactivators.
Hua et al 1995 Cloning and description of the SREBP-1 gene from human fetal brain DNA, proposes alternative splicing to account for variants. Variants are SREBP-1a and 1c.
Kim et al 1995 SREBP DNA binding domain has a tyrosine where there is noramlly a conserved arginine, this tyrosine allows binding to SRE sequences. Made mutations then assayed for DNA binding with DNA probes and electrophoretic mobility shift assay.
Sakai et al 1996 Sequential cleavage reqd. 1st (S1P) is rate limiting and regulated by sterols, unlike 2nd (S2P). Used western blot to show effect of sterols on S1P. Added intermediate product (found in mutants without S2P) to see if sterols regulated S2P.
Porter et al 1996 Hedgehog proteins are the only proteins to bind cholesterol covalently. By association this binding indicates an important role for cholesterol in development
Hasan et al 1994 Used cells requiring cholesterol, cells tended to revert to wild type. Transfected in human DNA and cells with no reliance on external cholesterol isolated and cultured. DNA was then assayed for a human repeat to indicate genes added. Led to S2P discovery
Sakai et al 1998 Found S1P gene. Generated an enzyme linked to the membrane by an S1P cleavage site, transfected the peptide into CHO cells lacking S1P and added cDNA from normal cells. Cells were then tested for enzymatic activity
Goldstein et al 1985 LDL receptors are recycled multiple times, carrying the ligand with them each time (overall lifespan 10-30 hrs). LDLR Apo binding region is homologous to C9 (which may therefore bind lipoproteins). -ve residues of LDLR bind +ve charged helix of ApoE
Grand-Perret et al 2001 Trial and improvement using luciferase linked to LDLR expression, identified SCAP ligands and showed that they reduced blood lipids. Odd direction to take as drugs increasing LDLR expression tend to cause steatosis through increase in HMGCoAR.
Hotamisligil et al 1993 In vivo, TNFa mRNA is upregulated in obesity (db/db mice) and TNFaR inhibitor increases insulin sensitivity. Fa/fa rats (=db/db) had TNFaR blocked by IgG. Cultured adipocytes downregulated GLUT4 in response to TNFa, reduced insulin response.
Uysal et al 1997 Compared ob/ob mice with TNFa KO + ob/ob double KO mice. Glucose tolerance (intraperitoneal test) improved in dbl KO, reduced plasma insulin in dbl KO. Insulin receptor more phosphorylated and therefore more active in dbl KO mice.
Mahley 1988 (only author) Review: ApoE is in VLDL and some HDL. Macrophages, astrocytes and hepatocytes make Apo. ApoE is cleaved by thrombin. After nerve damage ApoE is concentrated 100-200x around injury, made by macrophages, thought to clear fatty myelin.
Raper et al 2012 Review: Niacin has additive effects when added to statins. PCSK9 is an enzyme degrading LDLR inactivating mutations reduce LDL, antibodies in trials. Liver specific thyroid hormone analogue to incr LDLR (Eprotirome in trials).
Enger et al 2010 Shows roughly 4x greater risk of rhabdomyolysis when fibrates are added to statins (compared to the risk with statins alone)
Sachais et al 2005 LDL apheresis is safe and effective to use long term. Apheresis is selective removal of lipoproteins containing ApoB (LDL, vLDL). LDL levels return to normal after 12-14 days. Suitable for familial hypercholesterolaemia (Not for normal high cholesterol)
Cannon et al 2010 Inhibitors of cholesteryl ester transfer protein (normally transfers cholesterol from HDL to LDL) may be valuable in lowering LDL despite being developed against HDL, Anacetrapib is proceeding in trials despite previous failures due to incr mortality rate
Wetterau et al 1998 Microsomal triglyceride transfer protein inhibitors in development, aim to reduce secretion of LDL and VLDL (as seen in patients with MTP mutations - abetalipoproteinaemia). Shown here to work in rabbits.
Cuchel et al 2007 MTP inhibitors reduced LDL but caused fatty liver (probably unavoidable) and increased stool freq (may become steatorrhea - seen in patients with MTP mutations). Used lomitapide which now has orphan drug status.
Akdim et al 2010 Mipomersen trial - anti sense oligonucleotide against ApoB. Some side effects at injection site, flu-like symptoms plus some fatty liver (lowering LDL always seems to do this!)
Nissen et al 2003 Trial of ApoA1 Milano, effective at reducing plaque size (measured by intravenous ultrasound). Has since been passed around several companies but gone no further.
Shaw et al 2008 Human study: injecting recombinant HDL improves plaque characteristics. Less lipid, smaller macrophages seen after plaques were removed. Changes in plaque composition may have led to the improvement in ApoA1 milano studies, possible non-spec HDL effect.
Repa & Mangelsdorf 2002 Review of liver X receptors: Mice resist 100x incr cholesterol, upregulate cholesterol 7-alpha hydroxylase which is a target of LXRs and is rate limiting in bile acid synth. LXR ligands have been shown to reduce the size of atherosclerotic lesions.
Yang et al 2002 Mutant SCAP fails to bind INSIG-1, so is insensitive to sterol mediated inhibition of SREBP processing. INSIG-1 sequesters SCAP in ER. Compared co-ip of SCAP parteners in the presence and absence of a sequence reqd for sterol regulation, found INSIG.
Joesph et al 2002 Shows that synthetic LXR agonists are able to reduced the lesion size in mice moedls of atherosclerosis (LDLR KO and ApoE KO). Used male ApoE Ko, mixed gender LDLR KO, similar benefits so might not be gender bias. 12 week dosing.
Tangirala et al 2002 Irradiated mice to remove macrophages, transplanted in LXR KO macrophages and showed increased speed of lesion growth. LXRa and b were KO'd.
Saunders et al 2007 Meta-analysis of 31,000 patients over 37 studies showing no strong evidence for linkage of any one locus to BMI/BMI-defined obesity.
Created by: Jonmassie



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