Author: Ciancia, Marion ; Fraulob, Valérie ; Muramatsu, Shin-Ichi ; Rataj-Baniowska, Monika ; Dollé, Pascal ; de Lera, Angel R ; Alvarez, Rosana ; Baldassarro, Vito Antonio ; Krężel, Wojciech ; Geny, Bernard ; Charles, Anne-Laure ; Zinter, Nicolas ; Niewiadomska-Cimicka, Anna

Retinoic acid is a powerful regulator of brain development, however its postnatal functions only start to be elucidated. We show that retinoic acid receptor beta (RARβ), is involved in neuroprotection of striatopallidal medium spiny neurons (spMSNs), the cell type affected in different neuropsychiatric disorders and particularly prone to degenerate in Huntington disease (HD). Accordingly, the number of spMSNs was reduced in the striatum of adult Rarβ^-/- mice, which may result from mitochondrial dysfunction and neurodegeneration. Mitochondria morphology was abnormal in mutant mice whereas in cultured striatal Rarβ^-/- neurons mitochondria displayed exacerbated depolarization, and fragmentation followed by cell death in response to glutamate or thapsigargin-induced calcium increase. In vivo, Rarβ^-/- spMSNs were also more vulnerable to the mitochondrial toxin 3-nitropropionic acid (3NP), known to induce HD symptoms in human and rodents. In contrary, an RARβ agonist, AC261066, decreased glutamate-induced toxicity in primary striatal neurons in vitro, and diminished mitochondrial dysfunction, spMSN cell death and motor deficits induced in wild type mice by 3NP. We demonstrate that the striatopallidal pathway is compromised in Rarβ^-/- mice and associated with HD-like motor abnormalities. Importantly, similar motor abnormalities and selective reduction of spMSNs were induced by striatal or spMSN-specific inactivation of RARβ, further supporting a neuroprotective role of RARβ in postnatal striatum.

01 Mar 2022·BioFactorsQ3 · BIOLOGY

A retinoic acid receptor β2 agonist protects against alcohol liver disease and modulates hepatic expression of canonical retinoid metabolism genes

Q3 · BIOLOGY

Article

Author: Trasino, Steven E. ; Tang, Xiao‐Han ; Gross, Steven S. ; Qin, Lihui ; Attarwala, Nabeel ; Prishker, Carlos ; Chen, Qiuying ; Melis, Marta ; Gudas, Lorraine J.

AbstractAlcohol abuse reduces hepatic vitamin A (retinoids), reductions that are associated with progression of alcohol liver disease (ALD). Restoring hepatic retinoids through diet is contraindicated in ALD due to the negative effects of alcohol on retinoid metabolism. There are currently no drugs that can both mitigate alcohol‐driven hepatic retinoid losses and progression of ALD. Using a mouse model of alcohol intake, we examined if an agonist for the retinoic acid (RA) receptor β2 (RARβ2), AC261066 (AC261) could prevent alcohol‐driven hepatic retinoid losses and protect against ALD. Our results show that mice co‐treated with AC261 and alcohol displayed mitigation of ALD, including reduced macro, and microvesicular steatosis, and liver damage. Alcohol intake led to increases in hepatic centrilobular levels of ALDH1A1, a rate‐limiting enzyme in RA synthesis, and co‐localization of ALDH1A1 with the alcohol‐metabolizing enzyme CYP2E1, and 4‐HNE, a marker of oxidative stress; expression of these targets was abrogated in mice co‐treated with AC261 and alcohol. By RNA sequencing technology, we found that AC261 treatments opposed alcohol modulation of 68 transcripts involved in canonical retinoid metabolism. Alcohol modulation of these transcripts, including CES1D, CES1G, RBP1, RDH10, and CYP26A1, collectively favor hepatic retinoid hydrolysis and catabolism. However, despite this, co‐administration of AC261 with alcohol did not mitigate alcohol‐mediated depletions of hepatic retinoids, but did reduce alcohol‐driven increases in serum retinol. Our data show that AC261 protected mice against ALD, even though AC261 did not prevent alcohol‐mediated reductions in hepatic retinoids. These data warrant further studies of the anti‐ALD properties of AC261.

01 Dec 2021·Journal of Biological ChemistryQ2 · BIOLOGY

A retinoic acid receptor β2 agonist attenuates transcriptome and metabolome changes underlying nonalcohol-associated fatty liver disease

Q2 · BIOLOGY

Article

Author: Tang, Xiao-Han ; Jessurun, Jose ; Rappa, Andrew ; Zhang, Tuo ; Melis, Marta ; Gudas, Lorraine J ; Gross, Steven S ; Lu, Changyuan

Nonalcohol-associated fatty liver disease (NAFLD) is characterized by excessive hepatic accumulation of fat that can progress to steatohepatitis, and currently, therapeutic options are limited. Using a high-fat diet (HFD) mouse model of NAFLD, we determined the effects of the synthetic retinoid, AC261066, a selective retinoic acid receptor β2 (RARβ2) agonist, on the global liver transcriptomes and metabolomes of mice with dietary-induced obesity (DIO) using genome-wide RNA-seq and untargeted metabolomics. We found that AC261066 limits mRNA increases in several presumptive NAFLD driver genes, including Pklr, Fasn, Thrsp, and Chchd6. Importantly, AC261066 limits the increases in the transcript and protein levels of KHK, a key enzyme for fructose metabolism, and causes multiple changes in liver metabolites involved in fructose metabolism. In addition, in cultured murine hepatocytes, where exposure to fructose and palmitate results in a profound increase in lipid accumulation, AC261066 limits this lipid accumulation. Importantly, we demonstrate that in a human hepatocyte cell line, RARβ is required for the inhibitory effects of AC261066 on palmitate-induced lipid accumulation. Finally, our data indicate that AC261066 inhibits molecular events underpinning fibrosis and exhibits anti-inflammatory effects. In conclusion, changes in the transcriptome and metabolome indicate that AC261066 affects molecular changes underlying multiple aspects of NAFLD, including steatosis and fibrosis. Therefore, we suggest that AC261066 may have potential as an effective therapy for NAFLD.

100 Deals associated with AC-261066

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Preclinical	US	Sveikatal, Inc	23 Dec 2015
Fatty Liver	Preclinical	US	Sveikatal, Inc	23 Dec 2015

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