MicroRNA hsa-miR-1301-3p Regulates Human ADH6, ALDH5A1 and ALDH8A1 in the Ethanol-Acetaldehyde-Acetate Metabolic Pathway

Abstract

Alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) are vital enzymes involved in the metabolism of a variety of alcohols. Differences in the expression and enzymatic activity of human ADHs and ALDHs correlate with individual variability in metabolizing alcohols and drugs and in the susceptibility to alcoholic liver disease. MicroRNAs (miRNAs) function as epigenetic modulators to regulate the expression of drug-metabolizing enzymes. To characterize miRNAs that target ADHs and ALDHs in human liver cells, we carried out a systematic bioinformatics analysis to analyze free energies of the interaction between miRNAs and their cognate sequences in ADH and ALDH transcripts and then calculated expression correlations between miRNAs and their targeting ADH and ALDH genes using a public data base. Candidate miRNAs were selected to evaluate bioinformatic predictions using a series of biochemical assays. Our results showed that 11 miRNAs have the potential to modulate the expression of two ADH and seven ALDH genes in the human liver. We found that hsa-miR-1301-3p suppressed the expression of ADH6, ALDH5A1, and ALDH8A1 in liver cells and blocked their induction by ethanol. In summary, our results revealed that hsa-miR-1301-3p plays an important role in ethanol metabolism by regulating ADH and ALDH gene expression. SIGNIFICANCE STATEMENTSystematic bioinformatics analysis showed that 11 microRNAs might play regulatory roles in the expression of two alcohol dehydrogenase (ADH) and seven aldehyde dehydrogenase (ALDH) genes in the human liver. Experimental evidences proved that hsa-miR-1301-3p suppressed the expression of ADH6, ALDH5A1, and ALDH8A1 in liver cells and decreased their inducibility by ethanol.Disclaimer: The information in this paper is not an official guidance or policy statement of the US Food and Drug Administration (FDA). No official support or endorsement by the US FDA is intended or should be inferred.

Ethnic Differences in Serum Levels of microRNAs Potentially Regulating Alcohol Dehydrogenase 1B and Aldehyde Dehydrogenase 2

“…Regarding miRNAs regulating ADH1B expression, to the best of our knowledge so far, no reports are available in the literature. In human hepatoma cells, expression of ADH6 is reportedly suppressed by miR-1301-3p [13], while expression of ADH4 was increased by miR-148a-3p [14]. However, serum levels of miR-1301-3p and miR-148a-3p in the subjects of this study were too low for a comparison between Austrian and Japanese men.…”

“…Collectively, these findings suggest that miRNAs play an important role in the regulation of ALDH2 expression in several species. On the other hand, there are only two reports on regulation of alcohol dehydrogenase (ADH) by miRNA: in human hepatoma cells, miR-1301-3p suppressed expression of ADH6 [13], while miR-148a-3p promoted ADH4 expression [14]. To the best of our knowledge, there have been no reports on miRNAs that regulate expression of ADH1B.…”

A genetically encoded tool to increase cellular NADH/NAD+ ratio in living cells

“…ALDHs and other enzymes in this group are poorly biochemically studied dehydrogenases that use retinoic acid, gamma-aminobutyric acid, or betaine as a cosubstrate (47,48). Interestingly, ALDH8A1 expression was shown to be induced by ethanol in the liver, and this enzyme catalyzes the reaction of 2-aminomuconate semialdehyde and NAD + to produce 2-aminomuconate and NADH in the kynurenine pathway of tryptophan catabolism (49,50). In summary, our RNA-Seq experiments identified genes that are impacted by the NADH reductive stress induced by the novel genetically encoded tool, Ec STH.…”

Establishment of a 4-miRNA Prognostic Model for Risk Stratification of Patients With Pancreatic Adenocarcinoma

“…On the other hand, studies have shown that the down-regulation of miR-1301 is associated with the malignant clinical features and poor OS of patients with colorectal cancer (50), and the overexpression of miR-1301 has been shown to inhibit cell proliferation, migration and invasion (51). It is worth noting that miR-1301-3p has been widely studied in liver cancer, breast cancer and other cancer types for its anti-tumor effect (52)(53)(54)(55). Regarding miR-3655, wu et al showed that miR-3655 down-regulates CXCL5 and is used as a new diagnostic and prognostic marker for osteosarcoma (56).…”