| First Author | Kumar S | Year | 2019 |
| Journal | FASEB J | Volume | 33 |
| Issue | 3 | Pages | 3825-3840 |
| PubMed ID | 30540918 | Mgi Jnum | J:287927 |
| Mgi Id | MGI:6390465 | Doi | 10.1096/fj.201802015R |
| Citation | Kumar S, et al. (2019) Augmenter of liver regeneration protein deficiency promotes hepatic steatosis by inducing oxidative stress and microRNA-540 expression. FASEB J 33(3):3825-3840 |
| abstractText | Levels of augmenter of liver regeneration (ALR), a multifunctional protein, are reduced in steatohepatitis. ALR depletion from ALR (flox/flox)/Alb-Cre [ALR-L-knockout (KO)] mouse causes robust steatosis and apoptosis of hepatocytes, and pericellular fibrosis between 1 and 2 wk postbirth. Steatosis regresses by 4 wk upon reappearance of ALR-expressing hepatocytes. We investigated mechanisms of ALR depletion-induced steatosis. ALR-L-KO mice (1-, 2-, and 4 wk old) and Adeno-Cre-transfected ALR (flox/flox) hepatocytes were used for in vivo and in vitro studies. ALR depletion from hepatocytes in vivo downregulated peroxisome proliferator-activated receptor (PPAR)-alpha, carnitine palmitoyl transferase I (CPT1)a, peroxisomal membrane protein 70 (PMP70) (modest down-regulation), and acyl-CoA oxidase 1 (ACOX1). The markedly up-regulated (20X) novel microRNA-540 (miR-540) was identified to target PPARalpha, PMP70, ACOX1, and CPT1a. ALR depletion from primary hepatocytes increased oxidative stress, miR-540 expression, and steatosis and down-regulated PPARalpha, ACOX1, PMP70, and CPT1a expression. Anti-miR-540 mitigated ALR depletion-induced steatosis and prevented loss of PPARalpha, ACOX1, PMP70, and CPT1a expression. Antioxidant N-acetylcysteine and recombinant ALR (rALR) both inhibited ALR depletion-induced miR-540 expression and lipid accumulation in hepatocytes. Finally, treatment of ALR-L-KO mice with rALR between 1 and 2 wk prevented miR-540 expression, and arrested steatosis and fibrosis. We conclude that ALR deficiency-mediated oxidative stress induces generation of miR-540, which promotes steatosis by dysregulating peroxisomal and mitochondrial lipid homeostasis.-Kumar, S., Rani, R., Karns, R., Gandhi, C. R. Augmenter of liver regeneration protein deficiency promotes hepatic steatosis by inducing oxidative stress and microRNA-540 expression. |
