Kolesterol og galdesyrer i ME

Basisviden

Kolesterol indgår i cellens membran og påvirker cellesignalering. Kolesterol-molekylet er "byggesten" for en del hormoner, D-vitamin og galdesyrer. Kroppen tilføres kolesterol gennem maden, og resten af det kolesterol man skal bruge dannes i leveren. Ordet kolesterol kommer af det græske chole = galde og stear = fedt.

Galdesyrer dannes i leveren, som de primære galdesyrer:

• cholic acid (CA), dansk: kolsyre
• chenodeoxycholic acid (CDCA), dansk: kenodeoxykolsyre

De primære galdesyrer omsættes i tarmen af tarmbakterier til sekundære galdesyrer:

• deoxycholic acid (DCA)
• lithocholic acid (LCA).

Galdesalte er natrium og kalium salte af galdesyrer konjugeret (=bundet) med glycine og taurin.

Galdesyrer søger for, at vi kan opløse og optage det fedt vi spiser, og at vi kan optage de fedtopløselige vitaminer A, D, E og K.

ME forskning

Naviaux's undersøgelse af ME patienters metabolisme viste, at de biokemiske stiveje, der sørger for syntese af kolesterol og galdesyrer var dysregulerede. En metabolit i stivejene, lathosterol, var reduceret i blodet hos både mænd og kvinder i Kolesterolniveauet var normalt. Kvinderne havde nedsat niveau af galdesyren CDCA (1).

Germain's undersøgelse af kvindelige ME patienters metabolisme viste nedregulering af følgende metabollitter (2):

• glycocholate
• glycochenodeoxycholate
• glycolithocholate
• lithocholate
• sulfoglycolithocholate
• taurine

Vegas's epigenetiske studier af ME patienter afspejler en påvirkning af kolesterol/galdesyrer omsætning, idet følgende gener var epigenetiske ændrede (hypermethylerede) (3):

• SLC10A1, transportprotein fra familien af natrium/galdesyre cotransportere.
• OSTalpha, organic solute transporter, ligeledes et transport protein. Det er involveret i det enterohepatiske kredsløb.
• ABCC1, transportprotein med flere funktioner, bl.a. transport af glukuronider og sulfat konjugater af steroid hormoner og galdesalte.
• OSBPL10, oxysterol-binding protein familien er intracellulære lipid receptorer, der påvirker lipid ligevægten i cellen.
• NPC1, Nieman -Pick C1 protein, involveret i kolesterol transport inde i cellen.
• RAB11FIP1, RAB11 family interacting protein, involveret i kolesteroltransport inde i cellen, samtidig påvirker kolesterol lipidendocytose gennem RAB11.
• RABGAP1, RAB GTPase activating protein, stikord til RAB GTPaser er noget med lipider, phospholiper og membrantransport gennem endo- og exocytiske stiveje.
• CYB5R2, er involveret i kolesterol syntese, fedtsyre desaturation og elongation. CYB5R2 findes på kromosom 11, lige ved siden af genet PPFIBP2 (også hypermethyleret hos ME patienter). Det er en beta liprin, der er involveret i axon guidance og dannelse af synapser.

Det er oplagt, at dysregulerede kolesterol/galdesyrer stiveje kan forklare irritabel tarm, især ved store fedtrige måltider. Men kan dysreguleringerne i ME patienters metabolisme også påvirke de kolesterolholdige lipid rafts i cellemembranerne og herigennem cellesignalering?

Referencer:

1. Naviaux et al: Metabolic features of CFS. www.pnas.org/cgi/doi/10.1073/pnas.1607571113
2. Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371
3. Vega et al. DNA methylation Modifications associated with CFS. Plos One, aug 2014, vol 9, Issue 8, e104757

Kolesterolviden: Ikonen: Cellular cholesterol trafficking and compartmentalization. Nature Reviews, 9, Feb(2008).

Basisviden om gener: www.ncbi.nlm.nih.gov/gene

Phosphoinositides and ME

Germain et al:

"Another hypothesis that could be drawn from the pathway analysis concerns the glycerophospholipid metabolism, as we observed five altered metabolites involved in biological membrane composition. Phosphoinositides are phospholipids that play critical roles in the brain and the spinal cord and peripheral nerves, by being involved in cell regulation and membrane dynamics."

I believe this hypothesis is true and very important.

Phosphoinositides (PIs) are generated in the PI-cycle. The first step in the PI-cycle is the conversion of diacylglycerol (DAG) to phosphatidic acid (PA) via the enzyme diacylglycerol kinase (DGK).

The last step is genration of PIP2. PIP2 is involved in cell signaling, fx regulation of TRPs.

Glycerol-3-phosphate can be converted to lysophosphatidic acid, which can be converted to PA. Lipin (gene: LPIN) can convert PA to DAG.

Epigenetic changed genes in ME:

• DGKA (DGK-alpha) hypomethylated (2)
• DGKQ (DGK-theta) hypermethylated, with a negative foldchange (3)
• LPIN1 hypermethylated (2)

References:

1. Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371
2. Vega et al. DNA methylation Modifications associated with CFS. Plos One, aug 2014, vol 9, Issue 8, e104757
3. Brenu et al: Methylation profile of CD4+ T cells in CFS/ME. J. Clin Cell Immunol 5, 228

GPD2, the glycerophosphate-shuttle and ME

Glucose/pyruvate and lipid metabolism have been found dysregulated in ME (1, 2, 3)

Glycero-3-phosphate has been found up-regulated in ME (3).

The gene GPD2 codes mithochondrial glycerol-3-phosphate dehydrogenase (mGPDH).

mGPDH oxidizes glycerol-3-phosphate to dihydroxyacetone phosphate.

mGPDH is a very important enzyme of intermediary metabolism and as a component of glycerophosphate shuttle at the crossroads of glycolysis, oxidative phosphorylation and fatty acid metabolism (4).

These genes have been found epigenetic changed (hypermethylated) in ME (5):

• GPD2, glycerol-3-phosphate dehydrogenase 2
• SLC37A3, solute carrier family 37, glycerol-3-phosphate transporter
• DAK, dihydroxyacetone kinase 2 homolog

References:

1. Fluge et al: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy / chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376. Doi 10.1172/jci.insight.89276
2. Naviaux et al: Metabolic features of CFS. www.pnas.org/cgi/doi/10.1073/pnas.1607571113
3. Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371
4. Mracek et al: The function and the role of the mitochondrial glycerol-3-phosphate dehydrogenase in mammalian tissue. Biochimica et Biophysica Acta 1827, 2013, 401-410.
5. Vega et al. DNA methylation Modifications associated with CFS. Plos One, aug 2014, vol 9, Issue 8, e104757

IDH, GOT and ME

Fluge, Mella et al. have shown that ME is associated with defective oxidative metabolism - most likely involving impaired pyruvate dehydrogenase (PDH) function (1).

A study showed that PDH suppression shifted the source of lipogenic acetyl-CoA from glucose to glutamine, and this compensatory pathway required a net reductive isocitrate dehydrogenase (IDH) flux to produce a source of glutamine-derived acetyl-CoA for fatty acid. Levels of intra- and extracellular aspartate and alanine were enhanced (2).

Another study showed that inhibition of the mitochondrial pyruvate carrier in the retina caused accumulation of aspartate at the expense of glutamate. The mitochondrial glutamate oxoglutarate transaminase (GOT2) - also knowns as aspartate aminotransferase - became upregulated (3).

Expression of IDH-proteins (IDH3A, IDH3B and IDHP) and of GOT2 have been found upregulated in ME (4).

A proteomic study on cerebrospinal fluid from ME/CFS patients has shown (5):

• IDH1, CFS:2, normal value 4
• GOT1, CFS:39, normal value 29
• GOT2, CFS:1, normal value 6

Armstrong et al have shown increased aspartate, decreased glutamate and a potentially reduced provision of acetyl-CoA for the TCA-cycle (6).

Glutamate is important as a neurotransmitter and as a substrate for glutathione synthesis. Depletion of glutamate correlates with cell death in the retina (3).

Shungu et al. have found elevated ventricular lactate and decreased glutathione in CFS patients (7).

I have noticed that some ME patients develop an early age-related degeneration of the retina. Could dysregulated metabolism be involved?

The aspartate aminotransferase blood test (ASAT) is usually normal in ME patients. Could there be a local tissue-specific dysregulayion?

If glutamate decreases, what happens to the glutamate-NO-cGMP pathway in the brain?

References:

1. Fluge et al: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy / chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376. Doi 10.1172/jci.insight.89276
2. Rajagopalan et al. Metabolic plasticity maintains proliferation in pyruvate dehydrogenase deficient cells. Cancer & Metabolism (2015) 3:7
3. Du et al. Inhibition of mitochondrial pyruvate transport by Zaprinast couses massive accumulation of aspartate at the expence of glutamate in the retina. Journal of Biological Chemistry 288,50,dec 2013
4. Ciregia et al.
   Translational Psychiatry (2016), 6, e904
   doi:10.1038/tp.2016.184
5. Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issue 2
6. Armstrong et al. Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in CFS. Metabolomics, 2015, 11:1626-1639.
7. Dikoma C Shungu et al. Increased Ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder oathophysiology. NMR Biomed (2012)