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Retinoic acid regulates several genes in bile acid and lipid metabolism via upregulation of small heterodimer partner in hepatocytes.
Abstract
Retinoic acid (RA) affects multiple aspects of development, embryogenesis and cell differentiation processes. The liver is a major organ that stores RA suggesting that retinoids play an important role in the function of hepatocytes. In our previous studies, we have demonstrated the involvement of small heterodimer partner (SHP) in RA-induced signaling in a non-transformed hepatic cell line AML 12. In the present study, we have identified several critical genes in lipid homeostasis (Apoa1, Apoa2 and ApoF) that are repressed by RA-treatment in a SHP dependent manner, in vitro and also in vivo with the use of the SHP null mice. In a similar manner, RA also represses several critical genes involved in bile acid metabolism (Cyp7a1, Cyp8b1, Mdr2, Bsep, Baat and Ntcp) via upregulation of SHP. Collectively our data suggest that SHP plays a major role in RA-induced potential changes in pathophysiology of metabolic disorders in the liver.
Copyright 2014. Published by Elsevier B.V.
so retinoic acid causes problems with the bile acid formation. via upregulation of SHP. Estrogens do the same thing. Interestingly the CYP26 family the regulates retinoic acid also is affected negatively.
Estrogen-Induced Cholestasis Leads to Repressed CYP2D6 Expression in CYP2D6-Humanized Mice.
Abstract
Cholestasis activates bile acid receptor farnesoid X receptor (FXR) and subsequently enhances hepatic expression of small heterodimer partner (SHP). We previously demonstrated that SHP represses the transactivation of cytochrome P450 2D6 (CYP2D6) promoter by hepatocyte nuclear factor (HNF) 4. In this study, we investigated the effects of estrogen-induced cholestasis on CYP2D6 expression. Estrogen-induced cholestasis occurs in subjects receiving estrogen for contraception or hormone replacement, or in susceptible women during pregnancy. In CYP2D6-humanized transgenic (Tg-CYP2D6) mice, cholestasis triggered by administration of 17-ethinylestradiol (EE2) at a high dose led to 2- to 3-fold decreases in CYP2D6 expression. This was accompanied by increased hepatic SHP expression and subsequent decreases in the recruitment of HNF4 to CYP2D6 promoter. Interestingly, estrogen-induced cholestasis also led to increased recruitment of estrogen receptor (ER) , but not that of FXR, to Shp promoter, suggesting a predominant role of ER in transcriptional regulation of SHP in estrogen-induced cholestasis. EE2 at a low dose (that does not cause cholestasis) also increased SHP (by 50%) and decreased CYP2D6 expression (by 1.5-fold) in Tg-CYP2D6 mice, the magnitude of differences being much smaller than that shown in EE2-induced cholestasis. Taken together, our data indicate that EE2-induced cholestasis increases SHP and represses CYP2D6 expression in Tg-CYP2D6 mice in part through ER transactivation of Shp promoter.
Copyright 2015 by The American Society for Pharmacology and Experimental Therapeutics.
Guys listen !! its not going to work like this. We are so many , we are talking for 10 years in forums. Nothing solved.
Why dont we start a lawsuit against Roche ? or make a contact to a known medical university ALL TOGETHER ? we will never going to fix our problem like this. We need professional medical help !
Isnt there anybody who pressed a charge against Roche ? cant we prove it , cmon..
1 hour ago, SaffronAide said:Guys listen !! its not going to work like this. We are so many , we are talking for 10 years in forums. Nothing solved.
Why dont we start a lawsuit against Roche ? or make a contact to a known medical university ALL TOGETHER ? we will never going to fix our problem like this. We need professional medical help !
Isnt there anybody who pressed a charge against Roche ? cant we prove it , cmon..
There are hundreds of lawsuits filed every year against hoffman-la-roche, accutane side effects in particular, the dockets list thousands of names in district court of New Jersey alone. It's public information. Their lawyers fight cases year round.
12 hours ago, macleod said:There are hundreds of lawsuits filed every year against hoffman-la-roche, accutane side effects in particular, the dockets list thousands of names in district court of New Jersey alone. It's public information. Their lawyers fight cases year round.
So how in the fuck it can still be legal to sell isotretinoin? What needs to happen so it gets banned?
http://pharmrev.aspetjournals.org/content/pharmrev/50/2/315.full.pdf
I Think i found the Holy Grail in reducinbg the skin content of Retinoic acid. and it involves the CYP1A & CYP1A2 enzyme!
And we have a substance that can induce this! Indole 3 Carbinol!!!!
I'll review the document, though this side of my detox profile is not in the red so if indeed it is an issue, then I wonder what the cause is. As a side note, and I'll make a detailed post upon completing my trial, Calcium D Glucarate has done me great. I've only dosed 40g total this month and I'm taking a little break right now to review how I feel, but I'm definitely at my very best.
Gene & Variation | rsID | Alleles | Result |
CYP1A1*2C A4889G | rs1048943 | TT | -/- |
CYP1A1 m3 T3205C | rs4986883 | TT | -/- |
CYP1A1 C2453A | rs1799814 | GG | -/- |
CYP1A2 164A>C | rs762551 | AC | +/- |
Has anyone used polyenylphosphatidylcholine (PPC) to try to heal the liver?
It's listed in the wiki for hypervitaminosis A as something that can help. I've used Lecithin and choline before but this seems more liver specific.
8 hours ago, Pido said:So how in the fuck it can still be legal to sell isotretinoin? What needs to happen so it gets banned?
The FDA has discussed taking Roche off the market several times, but it never happened. Instead, warning labels were strengthened. However, this means nothing since most doctors dismiss the most troubling side effects as "rare" or even "unproven" despite Roche memos and studies out there.
As hard as it is, I have come to terms with the fact most people do seem relatively okay post-Accutane. I question if these people incur issues down the road, but the point still stands that the majority of people are not devastated by this drug as I have been or you have been. That being said, I wish this drug was restricted to ADULTS with treatment-resistant NODULAR acne, not just moderate acne that is persistent. I also wish doctors were more up-front about the risks, such as the fact Accutane kills brain, muscle, and bone cells. And that some people may suffer permanent cognitive impairment and depression. If ADULTS want to KNOWINGLY take that risk, then I am fine with it. (Even with the stipulations, people would turn to pharmacies overseas if they couldn't get it otherwise.)
In the mean time, we need scientific studies into why some of us are forever altered by this drug while others simply are not. In my opinion, that is a more productive focus.
On 9/25/2016 at 6:50 AM, TrueJustice said:I get my CBD oil from a local CBD consultant. It comes in a dropper, I drop 2-3 drops in a carrier oil (like olive, jojoba, etc) heat it up on the stove, and rub all over my body and into my scalp, fully saturating the tissues. Instant pain relief and skin hydration. It is a bit of a nuisance, but it's effective in my opinion and experience. After doing so you jump in the shower and wash it off. It absorbs into skin immediately. I also take it internally, most importantly. I live in Mass so getting CBD oil is possible in many locales.Also, I know it's obvious and I'm sure you already do it, but try to move as much as possible, brisk walking, hiking, etc. at the very least warm bathes, stretching, hot tub if so lucky to have access to one...CBD doesn't have THC in it, so it is technically legal. The Rick Simpson Oil that you read about has THC and CBD in very high quantities, and yes my cannabis consultant said it has extreme healing properties, but he doesn't make that...of course. It apparently gets you HIGHHH, like real high.
I think many of us are dealing with liver issues at the core of all of this. It's hard to say, buut from my research it still appears to be the link to all foundational issues. I'm gonna go back to flushing. , did 10 already. So daunting, but I did feel better after doing them
Where do you get CBD oil from?
Any brands you can recommend?In relation to your dry face - do you put CBD oil on it? or do you use it just on the body?
My circulation is horrendous too, plus I have bad varicose veins. On top of the eye floaters and all that crap, I'd say it's all related.
Is it from a clogged liver??
Was just having another watch of that '8 tips to curing accutane sides' video, and one thing I've not tried is liquid vitamin A.
Anyone given this a go in liquid form? I seem to do ok taking cod liver oil, but it doesn't restore my night vision (I've still got zero night vision 6 years post tane).
Apparently vitamin A improves the absorption of B12 and I'm currently taking MB12 2mg daily, so thought I'd order some liquid A.
If you want to deplete your body of stored retinoids.... this is the paper
http://hbsn.amegroups.com/article/view/6877/7838
INDUCE CYPA1 ... cauliflower, brussell sprouts, etc. but I3C is the main weapon in this
It is an AHR agonist.
not only does I3C(Indole 3 Carbinol) induce CYPA1... it also induces the UGT enzymes
it also lowers estrogens
reverses liver fibrosis
It has been proposed that aside from functioning as a xeno-sensor, the AhR has an important physiological role in regulating fundamental metabolic processes (13). Naturally occurring agonists of AhR are reported to include indole-containing compounds such as indole-3-carbinol, tryptophan photoproducts, tetrapyroles such as bilirubin and biliverdin, and possibly, arachidonic acid metabolites, however the physiological relevance of each of these remains unclear (12). 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is generally accepted to be an endogenous ligand for AhR (14,15).
On binding to one of its ligands, the AhR can regulate expression of a variety of genes including primarily those encoding cytochrome P450 (CYP) enzymes. CYP1A1, CYP1A2, CYP1B1 and CYP2S1 are well-studied AhR target genes which are induced upon AhR agonist exposure (2,7,12). Recent studies have revealed that at least a dozen additional genes encoding xenobiotic metabolizing enzymes, including phase I and II enzymes, and phase III transporters, collectively referred to as the AhR gene battery, are specifically induced as a result of AhR activation upon ligand binding. These include isoforms of aldehyde dehydrogenases (Aldh7a1), glutathione transferases (Gstm3), sulfotransferases (Sult5a1), UDP-glucuronosyltransferases (Ugt1a1, Ugt1a6, Ugt1a9, Ugt2b35), solute carrier (Slcs) and ATP binding cassette (Mrp4) transporter proteins (4,5,12,16-18). Flavin-containing monooxygenases (Fmo2andFmo3) that were earlier thought to be uninducible, have now been convincingly shown to be highly induced in an AhR-dependent manner (19,20).
canthaxanthin and astaxanthin are also strong AHr inducers
As for phase II detoxification enzymes, retinoids, including ATRA, 9CRA, as well as the RAR panagonist 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (TTNPB, arotinoid acid) have been shown to suppress, in a concentration-dependent manner, UDP-glucuronosyltransferase 2B7 isoform (UGT2B7) mRNA expression in Caco-2 cells (64). This regulation may represent an example of a negative feedback relationship between retinoids and xenobiotics, taking into consideration that UGT2B7 was shown to be the only UGT isoform capable of catalyzing glucuronidation of ATRA and its oxidized metabolites, including 4-OH-ATRA, 4-oxo-ATRA and 5,6-epoxy-ATRA (65). The formation of these glucuronides renders the retinoids water soluble and results in their elimination in the urine.
14 minutes ago, tryingtohelp2014 said:If you want to deplete your body of stored retinoids.... this is the paper
http://hbsn.amegroups.com/article/view/6877/7838
INDUCE CYPA1 ... cauliflower, brussell sprouts, etc. but I3C is the main weapon in this
It is an AHR agonist.
not only does I3C(Indole 3 Carbinol) induce CYPA1... it also induces the UGT enzymes
it also lowers estrogens
reverses liver fibrosisIt has been proposed that aside from functioning as a xeno-sensor, the AhR has an important physiological role in regulating fundamental metabolic processes (13). Naturally occurring agonists of AhR are reported to include indole-containing compounds such as indole-3-carbinol, tryptophan photoproducts, tetrapyroles such as bilirubin and biliverdin, and possibly, arachidonic acid metabolites, however the physiological relevance of each of these remains unclear (12). 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is generally accepted to be an endogenous ligand for AhR (14,15).
On binding to one of its ligands, the AhR can regulate expression of a variety of genes including primarily those encoding cytochrome P450 (CYP) enzymes. CYP1A1, CYP1A2, CYP1B1 and CYP2S1 are well-studied AhR target genes which are induced upon AhR agonist exposure (2,7,12). Recent studies have revealed that at least a dozen additional genes encoding xenobiotic metabolizing enzymes, including phase I and II enzymes, and phase III transporters, collectively referred to as the AhR gene battery, are specifically induced as a result of AhR activation upon ligand binding. These include isoforms of aldehyde dehydrogenases (Aldh7a1), glutathione transferases (Gstm3), sulfotransferases (Sult5a1), UDP-glucuronosyltransferases (Ugt1a1, Ugt1a6, Ugt1a9, Ugt2b35), solute carrier (Slcs) and ATP binding cassette (Mrp4) transporter proteins (4,5,12,16-18). Flavin-containing monooxygenases (Fmo2andFmo3) that were earlier thought to be uninducible, have now been convincingly shown to be highly induced in an AhR-dependent manner (19,20).
canthaxanthin and astaxanthin are also strong AHr inducers
So maybe then, I'm on the right track by dosing Clacium D Glucarate. I also have 10g of Diindolylmethane (DIM) at home, which is a component of I3C, so I'll add 100mg of it daily to my 3x 1g of CdG, and see how I do.
5 days of fasting can depleteserum concentrations of all-trans, 13-cis retinoic acids and retinol by 20%.
QuoteDecreasing serum concentrations of all-trans, 13-cis retinoic acids and retinol during fasting and caloric restriction.
Abstract
OBJECTIVES:
To investigate the effects of caloric restriction on the serum concentrations of retinoids in man.
DESIGN:
Samples were drawn before and during caloric restriction by fasting or 4-6 weeks after gastric surgery.
SUBJECTS:
The fasting group included 17 healthy subjects (11 women and six men) and 16 obese patients (10 women and six men) who underwent bariatric surgery (vertical banded gastroplasty).
MAIN OUTCOME MEASURES:
Serum concentrations of all-trans, 13-cis, 4-oxo-13-cis retinoic acids and retinol.
RESULTS:
The serum concentrations of retinol, all-trans and 13-cis retinoic acids decreased by about 20% after 5 days of fasting. After gastroplasty, the serum concentration of retinol, all-trans, 13-cis retinoic acids, retinol-binding protein and transthyretin also decreased to a similar extent after 1 month. In both groups we found a correlation between the delta values of 13-cis retinoic acid and its metabolite 4-oxo-13-cis retinoic acid. In all subjects there were also correlations between the delta values of the retinoids. However, these correlations were comparatively weak (e.g. r2 = 0.36 for retinol--all-trans retinoic acid). The change in retinoid concentrations did not correlate to the change of weight or body mass index.
CONCLUSION:
Our results support the hypothesis that serum retinol is one of the determinants of serum concentrations of all-trans and 13-cis retinoic acid and that the catabolism of 13-cis retinoic acid is not affected by fasting. However, in the individual case, S-Retinol is a poor predictor of S-All-trans retinoic acid.
- PMID:
- 12603506
I used B12 and folate before with no benefit. It's only after I added 500 mg Methionine a day, that I saw improvement in my crippling depression and fatigue. The effects are not cummulative though. If I don't take all 3 first thing in the morning, all those problems come back.
I get a noticeable energy boost from Biotin but it's hit or miss. If I take too much, I start getting sides like nausea and dizziness. I was getting a lot of fungal related problems and Dandruff, which biotin also helped clear.
13 hours ago, MonsterDiesel said:I used B12 and folate before with no benefit. It's only after I added 500 mg Methionine a day, that I saw improvement in my crippling depression and fatigue. The effects are not cummulative though. If I don't take all 3 first thing in the morning, all those problems come back.
I get a noticeable energy boost from Biotin but it's hit or miss. If I take too much, I start getting sides like nausea and dizziness. I was getting a lot of fungal related problems and Dandruff, which biotin also helped clear.
What sort of folate supplement do you take?
Is it methylfolate??
22 hours ago, tryingtohelp2014 said:If you want to deplete your body of stored retinoids.... this is the paper
http://hbsn.amegroups.com/article/view/6877/7838
INDUCE CYPA1 ... cauliflower, brussell sprouts, etc. but I3C is the main weapon in this
It is an AHR agonist.
not only does I3C(Indole 3 Carbinol) induce CYPA1... it also induces the UGT enzymes
it also lowers estrogens
reverses liver fibrosisIt has been proposed that aside from functioning as a xeno-sensor, the AhR has an important physiological role in regulating fundamental metabolic processes (13). Naturally occurring agonists of AhR are reported to include indole-containing compounds such as indole-3-carbinol, tryptophan photoproducts, tetrapyroles such as bilirubin and biliverdin, and possibly, arachidonic acid metabolites, however the physiological relevance of each of these remains unclear (12). 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is generally accepted to be an endogenous ligand for AhR (14,15).
On binding to one of its ligands, the AhR can regulate expression of a variety of genes including primarily those encoding cytochrome P450 (CYP) enzymes. CYP1A1, CYP1A2, CYP1B1 and CYP2S1 are well-studied AhR target genes which are induced upon AhR agonist exposure (2,7,12). Recent studies have revealed that at least a dozen additional genes encoding xenobiotic metabolizing enzymes, including phase I and II enzymes, and phase III transporters, collectively referred to as the AhR gene battery, are specifically induced as a result of AhR activation upon ligand binding. These include isoforms of aldehyde dehydrogenases (Aldh7a1), glutathione transferases (Gstm3), sulfotransferases (Sult5a1), UDP-glucuronosyltransferases (Ugt1a1, Ugt1a6, Ugt1a9, Ugt2b35), solute carrier (Slcs) and ATP binding cassette (Mrp4) transporter proteins (4,5,12,16-18). Flavin-containing monooxygenases (Fmo2andFmo3) that were earlier thought to be uninducible, have now been convincingly shown to be highly induced in an AhR-dependent manner (19,20).
canthaxanthin and astaxanthin are also strong AHr inducers
As for phase II detoxification enzymes, retinoids, including ATRA, 9CRA, as well as the RAR panagonist 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (TTNPB, arotinoid acid) have been shown to suppress, in a concentration-dependent manner, UDP-glucuronosyltransferase 2B7 isoform (UGT2B7) mRNA expression in Caco-2 cells (64). This regulation may represent an example of a negative feedback relationship between retinoids and xenobiotics, taking into consideration that UGT2B7 was shown to be the only UGT isoform capable of catalyzing glucuronidation of ATRA and its oxidized metabolites, including 4-OH-ATRA, 4-oxo-ATRA and 5,6-epoxy-ATRA (65). The formation of these glucuronides renders the retinoids water soluble and results in their elimination in the urine.
Ok so i dont understand all the technical stuff, so in summary what supplements should I take to detox this poison, at what doses?
Sometimes it can't, in that case you need to help it by stopping ingestion of toxins, avoiding stress and maximizing nutrition - or even fasting so as to give the body 'space' to do what it's got to do
Any doctor that tells you otherwise is just brainwashed or trying to make money out of you
We were nearly all in our teens/early twenties when we participated in this insane experiment a time when our powers for recovery are at a maximum
Nevertheless, most people dont seem to recover (not fully anyway) that shows you just how strong thepoison is and just how messed up the medical industry is just now
Thats why ED is so widespread today, its not because we are all taking substances that affect libido its because a drop in libido is a symptom of being unhealthy and a lot of people are unhealthy today
So you have to try and get healthy again, not take some magical substance, but you also have to be prepared to accept that there might not be a way back
Interesting results on bloodwork that just arrived today... on the normal male hormone panel... my Estradial was normal... but on the Total estrogen test... im High! Testosterone on the lower end. LH and FSH both on the lower end. my Vitamin D has stayed in range after stopping supplementation.
my copper levels have dropped again after 0 supplementation.... this is after getting them back into range, then stopping.
Im telling you, there is something here with the liver. copper/vitamin A levels... estrogen dominance. I really think that the Copper/retinoid balance is thrown off. it could be a sign of a clogged liver full of retinoids.
the plan now is to take I3C,DIM and calcium D glucarate.... eat a lot of brussel sprouts, cauliflower etc. to fix the estrogen problem. A few of the boards have come to the conclusion that accutane is a powerful Oestrogen.
Anyone with ED problems, low libido after accutane... i would advise to get a TOTAL ESTROGEN test. they even have a more precise one that breaks down specific E1 E2 E3 levels... something similar to this...
Since my Estradial is in the normal range... that must mean my Estrone levels are sky high??
Estradiol is important in regulating the female menstrual cycle and is used in the production of menstrual tissue. Estradiol levels are normally higher at the beginning of the menstrual cycle and lower at the end of the menstrual cycle. Once a woman has experienced menopause, the level of estradiol in her blood greatly decreases. Estradiol is present in both males and females (though much higher levels are seen in females) and is found in almost all mammals and fish that have a backbone.
Estriol is only seen in the blood in large amounts during pregnancy. When a woman is not pregnant she will have levels of estriol in her blood that are very similar to the levels of estriol in the blood of males or women after menopause. During pregnancy the placenta produces estriol, and levels continue to rise until the end of the pregnancy.
Estrone levels are lower than estradiol and estriol levels in fertile women. Estrone is at its highest level during pregnancy and is thought to be the cause of breast tenderness, nausea, and painful muscle cramping in women. Men also produce estrone. Abnormally high levels of estrone in men has been linked to anorexia nervosa, vomiting, and erectile dysfunction. In women who are post-menopausal, estrone is the most prevalent estrogen hormone.
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On 9/30/2016 at 12:21 AM, tryingtohelp2014 said:Interesting results on bloodwork that just arrived today... on the normal male hormone panel... my Estradial was normal... but on the Total estrogen test... im High! Testosterone on the lower end. LH and FSH both on the lower end. my Vitamin D has stayed in range after stopping supplementation.
my copper levels have dropped again after 0 supplementation.... this is after getting them back into range, then stopping.
Im telling you, there is something here with the liver. copper/vitamin A levels... estrogen dominance. I really think that the Copper/retinoid balance is thrown off. it could be a sign of a clogged liver full of retinoids.
the plan now is to take I3C,DIM and calcium D glucarate.... eat a lot of brussel sprouts, cauliflower etc. to fix the estrogen problem. A few of the boards have come to the conclusion that accutane is a powerful Oestrogen.
Anyone with ED problems, low libido after accutane... i would advise to get a TOTAL ESTROGEN test. they even have a more precise one that breaks down specific E1 E2 E3 levels... something similar to this...
Since my Estradial is in the normal range... that must mean my Estrone levels are sky high??
Estradiol is important in regulating the female menstrual cycle and is used in the production of menstrual tissue. Estradiol levels are normally higher at the beginning of the menstrual cycle and lower at the end of the menstrual cycle. Once a woman has experienced menopause, the level of estradiol in her blood greatly decreases. Estradiol is present in both males and females (though much higher levels are seen in females) and is found in almost all mammals and fish that have a backbone.
Estriol is only seen in the blood in large amounts during pregnancy. When a woman is not pregnant she will have levels of estriol in her blood that are very similar to the levels of estriol in the blood of males or women after menopause. During pregnancy the placenta produces estriol, and levels continue to rise until the end of the pregnancy.
Estrone levels are lower than estradiol and estriol levels in fertile women. Estrone is at its highest level during pregnancy and is thought to be the cause of breast tenderness, nausea, and painful muscle cramping in women. Men also produce estrone. Abnormally high levels of estrone in men has been linked to anorexia nervosa, vomiting, and erectile dysfunction. In women who are post-menopausal, estrone is the most prevalent estrogen hormone.
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This 13C and DIM - does a doctor need to prescribe it??
Or can we all just buy it on Internet?