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Fig. 1 | Orphanet Journal of Rare Diseases

Fig. 1

From: Cholbam® and Zellweger spectrum disorders: treatment implementation and management

Fig. 1

Adapted from Gonzales et al. [13], with permission from Elsevier

Disrupted bile acid synthesis in patients with ZSD and CA mechanism of action. CA, cholic acid; CDCA, chenodeoxycholic acid; CYP7A1, cytochrome P450 7A; LRH-1, liver receptor homolog 1; SHP-1, small heterodimeric partner 1. A Disrupted bile acid synthesis in patients with ZSD. In the absence of functional peroxisomes, there is a deficiency of primary C24-bile acids, which subsequently results in the disruption of the negative feedback loop (dotted lines) that maintains bile acid homeostasis under normal physiological conditions. Increased transcription of CYP7A1 causes a build-up of C27-bile acid intermediates, which have been shown to be cytotoxic. Additionally, deficiency in primary bile acids causes impaired bile flow and cholestasis, as well as reduced absorption of dietary fats and fat-soluble vitamins. B CA mechanism of action in patients with ZSD. Introduction of exogenous CA restores levels of the primary bile acids, improves bile flow and absorption, and reactivates the negative feedback loop, which, via repression of CYP7A1, reduces levels of the C27-bile acid intermediates.

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