HDL cholesterol protein low in MS

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HDL cholesterol protein low in MS

Postby cheerleader » Fri Nov 22, 2013 10:33 am

New research, presented at the annual meeting of the Society of Neuroscience, finds a link to the level of a cholesterol transport protein and MS disease severity.
http://www.medscape.com/viewarticle/814798
ApoA1 is the main structural protein found in HDL, or what we call "good" cholesterol, and it is found to be low in pwMS.
Blood levels of the reverse cholesterol transport protein apolipoprotein A1 (ApoA1) are low in patients with multiple sclerosis (MS) and correlate with disease severity, new research shows.
ApoA1 is the most abundant component of high-density lipoprotein cholesterol and is known to protect against inflammation.
Dr. Gardner and colleagues investigated ApoA1 levels in 53 patients with relapsing-remitting MS, 50 with secondary progressive MS, 53 with primary progressive MS, and 57 healthy controls. "Remarkably, all MS patients had less ApoA1 than controls," they report in a meeting abstract.
ApoA1 was reduced by approximately 25% in patients with relapsing-remitting MS, 50% in those with secondary progressive MS, and 75% in patients with primary progressive MS, the most severe form of the disease.


However, this is not unique to MS--- and shouldn't be "remarkable" to researchers.
low levels of ApoA1 are also found in Alzheimer's and Parkinson's, and releated to disease severity.

More on the connection of blood, diseases of neurodgeneration, and how to improve HDL levels here:

http://ccsviinms.blogspot.com/2013/11/g ... brain.html

cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Re: HDL cholesterol protein low in MS

Postby Annesse » Fri Nov 22, 2013 11:58 pm

Under the thread "Some Interesting Connections" I posted information on the elvated levels of homocysteine found in patients with MS (for anyone who hasn't seen the thread).

Here are a few studies that show homocysteine reduces apolipoprotein A.


Circ Res. 2006 Mar 3;98(4):564-71. Epub 2006 Jan 26.
Elevated homocysteine reduces apolipoprotein A-I expression in hyperhomocysteinemic mice and in males with coronary artery disease.
Mikael LG, Genest J Jr, Rozen R.

Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional or genetic disturbances in homocysteine metabolism. A polymorphism in methylenetetrahydrofolate reductase (MTHFR) is the most common genetic cause of mild hyperhomocysteinemia. To examine mechanisms by which an elevation in plasma homocysteine leads to vascular disease, we first performed microarray analyses in livers of Mthfr-deficient mice and identified differentially expressed genes that are involved in lipid and cholesterol metabolism. Microarrays and RT-PCR showed decreased mRNA for apolipoprotein A (ApoA)-IV and for ApoA-I and increased mRNA for cholesterol 7alpha hydroxylase (Cyp7A1) in Mthfr(+/-) mice compared with Mthfr(+/+) mice. Western blotting revealed that ApoA-I protein levels in liver and plasma of Mthfr(+/-) mice were 52% and 62% of levels in the respective tissues of Mthfr(+/+) mice. We also performed Western analysis for plasma ApoA-I protein levels in 60 males with coronary artery disease and identified a significant (P<0.01) negative correlation (-0.33) between ApoA-I and plasma homocysteine levels. This cohort also displayed a negative correlation (-0.24, P=0.06) between high-density lipoprotein cholesterol and plasma homocysteine. Treatment of HepG2 cells with supraphysiological levels of 5 mmol/L homocysteine reduced peroxisome proliferator-activated receptor (PPAR) alpha and ApoA-I protein levels and decreased ApoA-I promoter activity. Transfection with a PPARalpha construct upregulated ApoA-I and MTHFR. Our results suggest that hyperhomocysteinemia may increase risk of atherosclerosis by decreasing expression of ApoA-I and increasing expression of CYP7A1





Circ Res. 2006 Sep 15;99(6):598-606. Epub 2006 Aug 24.
Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I Protein synthesis and enhancing HDL cholesterol clearance.
Liao D, Tan H, Hui R, Li Z, Jiang X, Gaubatz J, Yang F, Durante W, Chan L, Schafer AI, Pownall HJ, Yang X, Wang H.
SourceDepartment of Medicine, Baylor College of Medicine, Houston, TX, USA.

We previously reported that hyperhomocysteinemia (HHcy), an independent risk factor of coronary artery disease (CAD), is associated with increased atherosclerosis and decreased plasma high-density lipoprotein cholesterol (HDL-C) in cystathionine beta-synthase-/apolipoprotein E-deficient (CBS(-/-)/apoE(-/-)) mice. We observed that plasma homocysteine (Hcy) concentrations are negatively correlated with HDL-C and apolipoprotein A1 (apoA-I) in patients with CAD. We found the loss of large HDL particles, increased HDL-free cholesterol, and decreased HDL protein in CBS(-/-)/apoE(-/-) mice, and attenuated cholesterol efflux from cholesterol-loaded macrophages to plasma in CBS(-/-)/apoE(-/-) mice. ApoA-I protein was reduced in the plasma and liver, but hepatic apoA-I mRNA was unchanged in CBS(-/-)/apoE(-/-) mice. Moreover, Hcy (0.5 to 2 mmol/L) reduced the levels of apoA-I protein but not mRNA and inhibited apoA-1 protein synthesis in mouse primary hepatocytes. Further, plasma lecithin:cholesterol acyltransferase (LCAT) substrate reactivity was decreased, LCAT specific activity increased, and plasma LCAT protein levels unchanged in apoE(-/-)/CBS(-/-) mice. Finally, the clearance of plasma HDL cholesteryl ester, but not HDL protein, was faster in CBS(-/-)/apoE(-/-) mice, correlated with increased scavenger receptor B1, and unchanged ATP-binding cassette transporter A1 protein expression in the liver. These findings indicate that HHcy inhibits reverse cholesterol transport by reducing circulating HDL via inhibiting apoA-I protein synthesis and enhancing HDL-C clearance


Clin Chem Lab Med. 2007;45(12):1652-9.
Hyperhomocysteinemia and high-density lipoprotein metabolism in cardiovascular disease.
Liao D, Yang X, Wang H.
SourceDepartment of Surgery, Baylor College of Medicine, Houston, TX, USA.


Hyperhomocysteinemia (HHcy) is a significant and independent risk factor for cardiovascular disease (CVD) and the underlying mechanism is unclear. We and others have reported that homocysteine (Hcy) is inversely correlated with plasma high-density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apoA-I) in patients with coronary heart disease (CHD). We confirmed this negative correlation in mice with targeted deletions of the genes for apolipoprotein E (apoE) and cystathionine beta-synthase (CBS). Severe HHcy (plasma Hcy 210 micromol/L) accelerates spontaneous arthrosclerosis in the CBS(-/-)/apoE(-/-) mice, reduces the concentration of circulating HDL, apoA-I, and large HDL particles, inhibits HDL function, and enhances HDL-C clearance. We have demonstrated further that Hcy (0.5-2 mmol/L) reduces apoA-I protein synthesis and secretion, but not RNA transcription in mouse primary hepatocytes. A different mechanism was proposed based on studies using the HepG2 cells showing that Hcy (5-10 mmol/L) inhibits apoA-I transcription via peroxisome proliferator-activated receptor-alpha (PPARalpha)-inhibition-dependent and -independent mechanisms. These studies suggest that Hcy-induced HDL-C and apoA-I inhibition represent a novel mechanism by which Hcy induces atherosclerotic CVD.
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Re: HDL cholesterol protein low in MS

Postby Annesse » Sat Nov 23, 2013 12:35 am

Taking this one step further, any disease that involves elevated homocysteine should have low levels of apolipoprotein A.

I posted the following study on the "Some Interesting Connections" thread about the association between MS and COPD due to an "inflammatory vulnerability" they have in common.

Increased prevalence of multiple sclerosis among COPD patients and their first-degree relatives: a population-based study.
Egesten A, Brandt L, Olsson T, Granath F, Inghammar M, Löfdahl CG, Ekbom A. 2008. Lung 186(3):173-8. doi: 10.1007/s00408-008-9081-y. Epub 2008 Mar 20.


“…In the COPD cohort, there was a more than twofold increased risk of MS compared with controls… This study indicates that COPD and MS have an inflammatory vulnerability in common...These diseases may share inflammatory pathways…”


Homocysteine would be the “inflammatory vulnerability” that both COPD and MS patients share. In the following study the researchers found that homocysteine was significantly elevated in COPD patients and was related to serum C-reactive protein (CRP), a common inflammatory marker, and COPD severity.

Plasma homocysteine is elevated in COPD patients and is related to COPD severity.
Seemungal TA, Lun JC, et al. 2007. Int J Chron Obstruct Pulmon Dis 2(3):313-21.

“…Plasma homocysteine is significantly elevated in COPD patients…and is related to serum CRP and COPD severity.”


So, we should expect to find that patients with COPD have low apolipoprotein A. As the following study confirms, apolipoprotein A is "significantly" reduced in patients with COPD.

Am J Respir Crit Care Med. 2010 May 15;181(10):1049-60. doi: 10.1164/rccm.200906-0857OC. Epub 2010 Jan 28.
Identification of lipocalin and apolipoprotein A1 as biomarkers of chronic obstructive pulmonary disease.Nicholas BL, Skipp P, Barton S, Singh D, Bagmane D, Mould R, Angco G, Ward J, Guha-Niyogi B, Wilson S, Howarth P, Davies DE, Rennard S, O'Connor CD, Djukanovic R.


RATIONALE: Much effort is being made to discover noninvasive biomarkers of chronic airway disease that might enable better management, predict prognosis, and provide new therapeutic targets.

OBJECTIVES: To undertake a comprehensive, unbiased proteomic analysis of induced sputum and identify novel noninvasive biomarkers for chronic obstructive pulmonary disease (COPD).

METHODS: Induced sputum was obtained from patients with COPD with a spectrum of disease severity and from control subjects. Two-dimensional gel electrophoresis and mass spectrometric identification of differentially expressed proteins were first applied to induced sputum from patients with GOLD stage 2 COPD and healthy smoker control subjects. Initial results thus obtained were validated by a combination of immunoassays (Western blotting and ELISA) applied to a large subject cohort. The biomarkers were localized to bronchial mucosa by immunohistochemistry.

MEASUREMENTS AND MAIN RESULTS: Of 1,325 individual protein spots identified, 37 were quantitatively and 3 qualitatively different between the two groups (P < 0.05%). Forty protein spots were subjected to tandem mass spectrometry, which identified 15 separate protein species. Seven of these were further quantified in induced sputum from 97 individuals. Using this sequential approach, two of these potential biomarkers (apolipoprotein A1 and lipocalin-1) were found to be significantly reduced in patients with COPD when compared with healthy smokers. Their levels correlated with FEV(1)/FVC, indicating their relationship to disease severity.

CONCLUSIONS: A potential role for apolipoprotein A1 and lipocalin-1 in innate defense has been postulated previously; our discovery of their reduction in COPD indicates a deficient innate defense system in airway disease that could explain increased susceptibility to infectious exacerbations.
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Re: HDL cholesterol protein low in MS

Postby cheerleader » Sat Nov 23, 2013 10:58 am

Thanks, Annesse. It was Jeff's high CRP levels, hypercoagulation, high SED and ESR rates at his diagnosis that began my search for the connection to the blood. His high levels came after a trip to high altitude---and these serum markers show up when the coagulation cascade is activated. They can also show up when someone has a bad diet, drinks too much, doesn't exercise, and with a host of other environmental factors.

But they can also be related to homocysteine levels, as you have been very thoroughly documenting.
I guess the main take away is that serum levels of these inflammatory components can affect the brain in all diseases of neurodeneration. It's important to step back and look at the big picture--

Jeff's neuro told me there was no connection---and that was (obviously) not true.
The blood and vasculature matter to the brain.
cheer
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