https://onlinelibrary.wiley.com/doi/10.1111/liv.13433
Seems atRA inhibits bile salt synthesis but also improves fibrotic markers in the liver. From the study it seems that people with liver cholestasis have an apparent vitamin A deficiency with lower serum retinol and impaired release from HSC’s which could mean higher levels in the liver that are not being released. There was however a lot of therapeutic effects with the administration of VA in animal studies.
A lot of the study went over my head but I’d recommend reading it as it seems to explain the role of retinol more in detail in the “Toxic Bile theory” and or liver cholestasis. Someone with a more in depth knowledge could provide better insight I’m sure.
Here’s a few interesting parts I highlighted :
“Nevertheless, the only study describing hepatic vitamin A levels in PBC patients showed that retinoids accumulate in HSCs.24Nyberg et al.24 confirmed that PBC patients have lower serum retinoid levels than controls and that these levels correlate with the stage of disease. Additionally, they found that HSCs are larger and more numerous in PBC patients in comparison with the controls. Also, while serum retinol binding protein (s-RBP) staining intensity was comparable to control intensity, staining intensity of cellular RBP (c-RBP) was significantly enhanced in PBC patients. This suggests that the release of retinoids from HSCs may be restrained in PBC. The lack of stimulatory effects of estradiol on the hepatic secretion of RBP during menopause may further explain why PBC affects primarily elderly women.5, 25 In 2000, Erickson et al.26 suggested that vitamin A toxicity may contribute to the aetiopathology of PBC. Intrahepatic cholestasis caused by vitamin A intoxication has been reported in two cases,27, 28 and interestingly, in one case hypervitaminosis A was cured by the application of UDCA.28”
“Jorgensen et al.29 conducted the largest study to date on serum retinoid levels in PSC patients, including 43 PSC patients enrolled in a study investigating the efficacy of UDCA and 77 pretransplant PSC patients. They found that 40% of patients in the UDCA trial group and 82% in the pre-transplant group suffered from vitamin A deficiency.”
“Since serum vitamin A levels do not seem to correlate with disease severity, it is questionable whether relative or absolute vitamin A deficiency is related to the pathogenesis of this disease. However, all of these studies were small, including between 720 and 7729 patients, and the hepatic retinoid content was not measured in any study.”
In Animals:
“the depletion of lipid droplets in HSCs was shown to be reversible through subcutaneous vitamin A injections, and fibrotic markers were reduced upon vitamin A administration. These findings suggest that vitamin A supplementation in vivo may attenuate hepatic fibrosis by reducing the transformation of HSCs into myofibroblasts, which is in accordance with results obtained in vitro with all-trans retinoic acid (atRA).31”
“Administration of vitamin A prior to or following BDL can potentially prevent a severe type of liver damage, by reducing the hepatic levels of fibrotic markers,30, 31 improving histological appearance of the liver,31 and inhibiting pathological ductular proliferation.30”
“atRA influences bile production since it was shown that in vitro it represses the activity of cytochrome p450 7A1 (CYP7A1), the rate-limiting enzyme in bile salt synthesis.36 In this study atRA repressed CYP7A1 more effectively than UDCA.”
“Retinoids could maybe even be more effective than UDCA, the only approved pretransplant therapy for chronic cholestatic disorders to date.”
From Conclusion:
“retinoids exert their potentially beneficial effect through different mechanisms: repression and prevention of hepatic fibrosis after liver injury through the inhibition of Ito cell transformation into myofibroblasts, modulation of the immunological response to hepatic damage through the regulation of expansion and apoptosis of myeloid cells, and the reduction of the toxicity of cholestasis through the inhibition of bile salt synthesis.”
Seems atRA inhibits bile salt synthesis but also improves fibrotic markers in the liver. From the study it seems that people with liver cholestasis have an apparent vitamin A deficiency with lower serum retinol and impaired release from HSC’s which could mean higher levels in the liver that are not being released. There was however a lot of therapeutic effects with the administration of VA in animal studies.
A lot of the study went over my head but I’d recommend reading it as it seems to explain the role of retinol more in detail in the “Toxic Bile theory” and or liver cholestasis. Someone with a more in depth knowledge could provide better insight I’m sure.
Here’s a few interesting parts I highlighted :
“Nevertheless, the only study describing hepatic vitamin A levels in PBC patients showed that retinoids accumulate in HSCs.24Nyberg et al.24 confirmed that PBC patients have lower serum retinoid levels than controls and that these levels correlate with the stage of disease. Additionally, they found that HSCs are larger and more numerous in PBC patients in comparison with the controls. Also, while serum retinol binding protein (s-RBP) staining intensity was comparable to control intensity, staining intensity of cellular RBP (c-RBP) was significantly enhanced in PBC patients. This suggests that the release of retinoids from HSCs may be restrained in PBC. The lack of stimulatory effects of estradiol on the hepatic secretion of RBP during menopause may further explain why PBC affects primarily elderly women.5, 25 In 2000, Erickson et al.26 suggested that vitamin A toxicity may contribute to the aetiopathology of PBC. Intrahepatic cholestasis caused by vitamin A intoxication has been reported in two cases,27, 28 and interestingly, in one case hypervitaminosis A was cured by the application of UDCA.28”
“Jorgensen et al.29 conducted the largest study to date on serum retinoid levels in PSC patients, including 43 PSC patients enrolled in a study investigating the efficacy of UDCA and 77 pretransplant PSC patients. They found that 40% of patients in the UDCA trial group and 82% in the pre-transplant group suffered from vitamin A deficiency.”
“Since serum vitamin A levels do not seem to correlate with disease severity, it is questionable whether relative or absolute vitamin A deficiency is related to the pathogenesis of this disease. However, all of these studies were small, including between 720 and 7729 patients, and the hepatic retinoid content was not measured in any study.”
In Animals:
“the depletion of lipid droplets in HSCs was shown to be reversible through subcutaneous vitamin A injections, and fibrotic markers were reduced upon vitamin A administration. These findings suggest that vitamin A supplementation in vivo may attenuate hepatic fibrosis by reducing the transformation of HSCs into myofibroblasts, which is in accordance with results obtained in vitro with all-trans retinoic acid (atRA).31”
“Administration of vitamin A prior to or following BDL can potentially prevent a severe type of liver damage, by reducing the hepatic levels of fibrotic markers,30, 31 improving histological appearance of the liver,31 and inhibiting pathological ductular proliferation.30”
“atRA influences bile production since it was shown that in vitro it represses the activity of cytochrome p450 7A1 (CYP7A1), the rate-limiting enzyme in bile salt synthesis.36 In this study atRA repressed CYP7A1 more effectively than UDCA.”
“Retinoids could maybe even be more effective than UDCA, the only approved pretransplant therapy for chronic cholestatic disorders to date.”
From Conclusion:
“retinoids exert their potentially beneficial effect through different mechanisms: repression and prevention of hepatic fibrosis after liver injury through the inhibition of Ito cell transformation into myofibroblasts, modulation of the immunological response to hepatic damage through the regulation of expansion and apoptosis of myeloid cells, and the reduction of the toxicity of cholestasis through the inhibition of bile salt synthesis.”
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