A hypothesis on UC/PSC

[Guest guest]

Dear All;

After reading the literature on PSC, IBD and immunology for the last

4 years, I would now like to propose a hypothesis on UC/PSC, based in

part on my two previous posts this evening.

I hypothesize that an as yet unidentified gut bacterium catalyzes

asymetric cleavage of beta-carotene (the normal dietary source of

vitamin A), to produce a retinoic acid derivative (apo14) that

inhibits the retinoid X receptor:

________________

Mol Endocrinol. 2007 Jan;21(1):77-88.

Asymmetric cleavage of beta-carotene yields a transcriptional

repressor of retinoid X receptor and peroxisome proliferator-

activated receptor responses.

Ziouzenkova O, Orasanu G, Sukhova G, Lau E, Berger JP, Tang G,

Krinsky NI, Dolnikowski GG, Plutzky J

Cardiovascular Division, Brigham and Women's Hospital, Havard

University, Boston, Massachusetts 02115, USA.

beta-Carotene and its metabolites exert a broad range of effects, in

part by regulating transcriptional responses through specific nuclear

receptor activation. Symmetric cleavage of beta-carotene can yield 9-

cis retinoic acid (9-cisRA), the natural ligand for the nuclear

receptor RXR, the obligate heterodimeric partner for numerous nuclear

receptor family members. A significant portion of beta-carotene can

also undergo asymmetric cleavage to yield apocarotenals, a series of

poorly understood naturally occurring molecules whose biologic role,

including their transcriptional effects, remains essentially unknown.

We show here that beta-apo-14'-carotenal (apo14), but not other

structurally related apocarotenals, represses peroxisome proliferator-

activated receptors (PPAR) and RXR activation and biologic responses

induced by their respective agonists both in vitro and in vivo.

During adipocyte differentiation, apo14 inhibited PPARgamma target

gene expression and adipogenesis, even in the presence of the potent

PPARgamma agonist BRL49653. Apo14 also suppressed known PPARalpha

responses, including target gene expression and its known

antiinflammatory effects, but not if PPARalpha agonist stimulation

occurred before apo14 exposure and not in PPARalpha-deficient cells

or mice. Other apocarotenals tested had none of these effects. These

data extend current views of beta-carotene metabolism to include

specific apocarotenals as possible biologically active mediators and

identify apo14 as a possible template for designing PPAR and RXR

modulators and better understanding modulation of nuclear receptor

activation. These results also suggest a novel model of molecular

endocrinology in which metabolism of a parent compound, beta-

carotene, may alternatively activate (9-cisRA) or inhibit (apo14)

specific nuclear receptor responses. PMID: 17008383.

________________

Because the retinoid X receptor is required for the activity of a

large number of other receptors in the liver, including PXR, PPARs,

VDR, RAR, and FXR, its inhibition by a compound like apo14 would

cause massive disruption of bile transport and detoxification, lipid

metabolism, and vitamin D signaling. As mentioned before, down-

regulation of PXR would lead to down-regulation of MDR1 and hence

increased susceptibility to xenobiotics, and increased inflammation,

and cholestasis. Because docosahexaenoic acid (DHA) can substitue for

9-cis retinoic acid as an activator of RXR, then fish oils rich in

DHA could potentially counteract the inhibitory action of apo14.

It's possible that a compound like apo14 could also interfere with

immune regulation in the gut, causing accumulation of inflammatory

Th17 cells at the expense of anti-inflammatory Tregs (see my earlier

posts this evening), perpetuating the inflammation, and eventually

causing vitamin A deficiency (common in IBD and PSC).

But a hypothesis should not be treated as fact. Rather it should be

subject to critical research and experimentation to prove it is

either right of wrong.

Best regards,

Dave

(father of (22); PSC 07/03; UC 08/03)