5-Aminolevulinic acid combined with sodium ferrous citrate (5-ALA/SFC) ameliorated liver injury in a murine acute graft-versus-host disease model by reducing inflammation responses through PGC1-α activation

Abstract

Acute graft-versus-host disease (aGvHD) remains lethal as a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). Inflammatory responses play an important role in aGvHD. 5-Aminolevulinic acid combined with sodium ferrous citrate (5-ALA/SFC) has been widely reported to have a major effect on the anti-inflammatory response; however, these effects in aGvHD models have never been reported. In this study, a murine aGvHD model was developed by transferring spleen cells from donor B6/N (H-2k b ) mice into recipient B6D2F1 (H-2k b/d ) mice. In addition to evaluating manifestations in aGvHD mice, we analyzed the serum ALT/AST levels, liver pathological changes, infiltrating cells and mRNA expression of inflammation-related cytokines and chemokines. 5-ALA/SFC treatment significantly ameliorated liver injury due to aGvHD and decreased the population of liver-infiltrating T cells, resulting in a reduced expression of pro-inflammatory cytokines and chemokines. Furthermore, the mRNA expression proliferator-activated receptor-γ coactivator (PGC-1α) was enhanced, which might explain why 5-ALA/SFC treatment downregulates inflammatory signaling pathways. Our results indicated that 5-ALA/SFC can ameliorate liver injury induced by aGvHD through the activation of PGC-1α and modulation of the liver mRNA expression of inflammatory-related cytokines and chemokines. This may be a novel strategy for treating this disease.

Mitochondrial Dysfunction-Associated Mechanisms in the Development of Chronic Liver Diseases

“…It accomplishes these multifaceted effects by linking itself to a variety of proteins that regulate cellular metabolism, such as peroxisome proliferator-activated receptors (PPARs), nuclear respiratory factor-1/2, farnesoid X receptor, liver X receptor, forkhead box protein O1 (FOXO1), sirtuin 1 (Sirt1), tumor protein p53 and hepatocyte nuclear factor 4. Wang et al showed that increasing PGC-1α mRNA expression stimulates mitochondrial activity and ameliorates liver injury by increasing the IL-10-mediated anti-inflammatory response [161]. Further studies revealed that PGC-1αmediated mitochondrial biogenesis plays a vital role in mitigating the high-fat diet-induced hepatic steatosis development [162].…”