Modulation of retinoid signaling: therapeutic opportunities in organ fibrosis and repair

Wang, Suya; Yu, Jianshi; Kane, Maureen A.; Moise, Alexander R.

doi:10.1016/j.pharmthera.2019.107415

Cited by 27 publications

(39 citation statements)

References 444 publications

(521 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Retinoic acid (RA) signaling is not only critical for organogenesis and patterning during development, but also important for the maintenance of tissue homeostasis after birth [ 52 ]. Therapies based on retinoids to augment RA signaling have been applied to treat various cancers and skin disorders [ 53 ]. Alternatively, reducing RA signaling by RORc inhibitors serves as potential therapeutics to combat autoimmune diseases [ 54 ], indicating that RA signaling-based therapies are context-dependent.…”

Section: Discussionmentioning

confidence: 99%

Aldh inhibitor restores auditory function in a mouse model of human deafness

Zhu

Gong

et al. 2020

PLoS Genet

View full text Add to dashboard Cite

Genetic hearing loss is a common health problem with no effective therapy currently available. DFNA15, caused by mutations of the transcription factor POU4F3, is one of the most common forms of autosomal dominant non-syndromic deafness. In this study, we established a novel mouse model of the human DFNA15 deafness, with a Pou4f3 gene mutation (Pou4f3Δ) identical to that found in a familial case of DFNA15. The Pou4f3(Δ/+) mice suffered progressive deafness in a similar manner to the DFNA15 patients. Hair cells in the Pou4f3(Δ/+) cochlea displayed significant stereociliary and mitochondrial pathologies, with apparent loss of outer hair cells. Progression of hearing and outer hair cell loss of the Pou4f3(Δ/+) mice was significantly modified by other genetic and environmental factors. Using Pou4f3(-/+) heterozygous knockout mice, we also showed that DFNA15 is likely caused by haploinsufficiency of the Pou4f3 gene. Importantly, inhibition of retinoic acid signaling by the aldehyde dehydrogenase (Aldh) and retinoic acid receptor inhibitors promoted Pou4f3 expression in the cochlear tissue and suppressed the progression of hearing loss in the mutant mice. These data demonstrate Pou4f3 haploinsufficiency as the main underlying cause of human DFNA15 deafness and highlight the therapeutic potential of Aldh inhibitors for treatment of progressive hearing loss.

show abstract

Section: Discussionmentioning

confidence: 99%

Aldh inhibitor restores auditory function in a mouse model of human deafness

Zhu

Gong

et al. 2020

PLoS Genet

View full text Add to dashboard Cite

show abstract

“…VA is also important during embryonic lung development (43) ; thus, the role in tissue repair in postnatal life is not surprising. A recent review highlights the potential role of VA and retinoic acid as possible therapeutic interventions to prevent pulmonary fibrosis following lung injury (44) , suggesting a role for VA in recovery from severe COVID-19 disease. Lipofibroblasts are the retinoid storage cells of the lung, similar to stellate cells of the liver (18) , and contain many components of the retinoid signalling pathway including receptors and binding proteins (45) .…”

Section: Vitamin a And Epithelial Barriersmentioning

confidence: 99%

Vitamin A in resistance to and recovery from infection: relevance to SARS-CoV2

Stephensen

2021

Br J Nutr

View full text Add to dashboard Cite

SARS-CoV2 infects respiratory epithelial cells via its cellular receptor angiotensin-converting enzyme 2 (ACE2), causing a viral pneumonia with pronounced inflammation resulting in significant damage to the lungs and other organ systems, including the kidneys, though symptoms and disease severity are quite variable depending on the intensity of exposure and presence of underlying conditions that may affect the immune response. The resulting disease, COVID-19, can cause multi-organ system dysfunction in patients requiring hospitalization and intensive care treatment. Serious infections like COVID-19 often negatively affect nutritional status and the resulting nutritional deficiencies may increase disease severity and impair recovery. One example is the viral infection measles, where associated vitamin A (VA) deficiency increases disease severity and appropriately timed supplementation during recovery reduces mortality and hastens recovery. VA may play a similar role in COVID-19. First, VA is important in maintaining innate and adaptive immunity to promote clearance of a primary infection as well as minimize risks from secondary infections. Second, VA plays a unique role in the respiratory tract, minimizing damaging inflammation, supporting repair of respiratory epithelium and preventing fibrosis. Third, VA deficiency may develop during COVID-19 due to specific effects on lung and liver stores caused by inflammation and impaired kidney function, suggesting that supplements may be needed to restore adequate status. Fourth, VA supplementation may counteract adverse effects of SARS-CoV2 on the angiotensin system as well as minimizing adverse effects of some COVID-19 therapies. Evaluating interactions of SARS-COV2 infection with VA metabolism may thus provide improved COVID-19 therapy.

show abstract

“…Retinol (vitamin A), a common component of a wide variety of nutritional supplements, is a signaling substance that plays an essential role in the body. Under normal conditions, retinol is stored almost in HSCs [ 7 ], but is mobilized toward extrahepatic storage sites during the progression of liver injuries, particularly those leading to fibrosis and cirrhosis [ 8 ]. However, the mechanism by which retinol is released from activated HSCs and affects hepatocytes has not been characterized.…”

Section: Introductionmentioning

confidence: 99%

Retinol from hepatic stellate cells via STRA6 induces lipogenesis on hepatocytes during fibrosis

et al. 2021

View full text Add to dashboard Cite

Background Hepatic stellate cells (HSCs) are activated in response to liver injury with TIF1γ-suppression, leading to liver fibrosis. Here, we examined the mechanism how reduction of TIF1γ in HSCs induces damage on hepatocytes and liver fibrosis. Method Lrat:Cas9-ERT2:sgTif1γ mice were treated Tamoxifen (TMX) or wild-type mice were treated Thioacetamide (TAA). HSCs were isolated from mice liver and analyzed role of Tif1γ. HepG2 were treated retinol with/without siRNA for Stimulated by retinoic acid 6 (STRA6) or Retinoic acid receptor(RAR)-antagonist, and LX2 were treated siTIF1γ and/or siSTRA6. TAA treated mice were used for evaluation of siSTRA6 effect in liver fibrosis. Results When we blocked the Tif1γ in HSCs using Lrat:Cas9-ERT2:sgTif1γ mice, retinol is distributed into hepatocytes. Retinol influx was confirmed using HepG2, and the increased intracellular retinol led to the upregulation of lipogenesis-related-genes and triglyceride. This effect was inhibited by a RAR-antagonist or knock-down of STRA6. In the LX2, TIF1γ-suppression resulted in upregulation of STRA6 and retinol release, which was inhibited by STRA6 knock-down. The role of STRA6-mediated retinol transfer from HSCs to hepatocytes in liver fibrosis was demonstrated by in vivo experiments where blocking of STRA6 reduced fibrosis. Conclusions Retinol from HSCs via STRA6 in response to injury with TIF1γ-reduction is taken up by hepatocytes via STRA6, leading to fat-deposition and damage, and liver fibrosis.

show abstract

Modulation of retinoid signaling: therapeutic opportunities in organ fibrosis and repair

Cited by 27 publications

References 444 publications

Aldh inhibitor restores auditory function in a mouse model of human deafness

Aldh inhibitor restores auditory function in a mouse model of human deafness

Vitamin A in resistance to and recovery from infection: relevance to SARS-CoV2

Retinol from hepatic stellate cells via STRA6 induces lipogenesis on hepatocytes during fibrosis

Contact Info

Product

Resources

About