The P300/CBP‐associating factor (PCAF), a histone acetyltransferase, is involved in metabolic and pathogenic diseases, particularly of the liver. The effects of PCAF on fine‐tuning liver diseases are extremely complex and vary according to different pathological conditions. This enzyme has dichotomous functions, depending on differently modified sites, which regulate the activities of various enzymes, metabolic functions, and gene expression. Here, we summarize the most recent findings on the functions and targets of PCAF in various metabolic and immunological processes in the liver and review these new discoveries and models of PCAF biology in three areas: hepatic metabolic syndrome, inflammatory disease, and cancer. Finally, we discuss the potential implications of these findings for therapeutic interventions in liver diseases.
The liver is the most essential organ for the metabolism of ammonia, in where most of ammonia is removed by urea and glutamine synthesis. Regulated by leucine, glutamate dehydrogenase (GDH) catalyzes the reversible inter-conversion of glutamate to ammonia. To determine the mechanism of leucine regulating GDH, pigs weighing 20 ± 1 kg were infused for 80 min with ammonium chloride or alanine in the presence or absence of leucine. Primary pig hepatocytes were incubated with or without leucine. In the in vivo experiments with either ammonium or alanine as the nitrogen source, addition of leucine significantly inhibited ureagenesis and promoted the production of glutamate and glutamine in the perfused pig liver (P < 0.05). Similarly, leucine stimulated GDH activity and inhibited sirtuin4 (SIRT4) gene expression (P < 0.01). Leucine could also activate mammalian target of rapamycin complex 1 (mTORC1) signaling (P < 0.05), as evidenced by the increased phosphorylation levels of ribosomal protein S6 kinase 1 (S6K1) and ribosomal protein S6 (S6). Interestingly, the leucine-induced mTORC1 pathway activation suitably correlated with increased GDH activity and decreased expression of SIRT4. Similar results were observed in primary cultured hepatocytes. Notably, leucine exerted no significant change in GDH activity in SIRT4-deficient hepatocytes (P > 0.05), while mTORC1 signaling was activated. Leucine exerted no significant changes in both GDH activity and SIRT4 gene expression in rapamycin treated hepatocytes (P > 0.05). In conclusion, L-leucine increases GDH activity and stimulates glutamate synthesis from different nitrogen sources by regulating mTORC1/SIRT4 pathway in the liver of pigs.
This study aimed to address the roles of divalent-cation transporter genes of Lactobacillus casei 2-9-5 in resisting hop bitter compound iso-a-acid. To determine the underlying mechanisms for Lactobacillus casei strains to resist iso-a-acid, RNA sequencing was performed for La. casei 2-9-5 and W2-9-5, which was an isolate of La. casei W2-9-5 derivative with a relatively weaker iso-a-acid resistance ability, in 0.012% iso-a-acid solution. Results indicated that its resistance of iso-a-acid was closely related to transmembrane transport, membrane composition and oxidative phosphorylation. Compared with La. casei W2-9-5, the expressions of the mntA, mntB and mntC genes were found to be significantly up-regulated in La. casei 2-9-5 and confirmed by RT-qPCR analysis. To examine the roles of these genes, recombinant plasmids harboring these genes were constructed and expressed in model bacteria Lactococcus lactis NZ3900. Relative to controls, the recombinant Lc. lactis containing mntB and mntC genes grew better under iso-a-acid pressure. Furthermore, the intracellular Mn 2þ concentration in La. casei 2-9-5 was much higher than that in La. casei W2-9-5. Together, the data support that manganese transporter genes mntB and mntC are involved in the iso-a-acid resistance ability of La. casei strains through enhancement of intracellular Mn 2þ concentrations.
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