title: Lamin aggregation is an early sensor of porphyria-induced liver injury.
abstract: Oxidative liver injury during steatohepatitis results in aggregation and transglutaminase-2 (TG2)-mediated crosslinking of the keratin cytoplasmic intermediate filament proteins (IFs) to form Mallory-Denk body (MDB) inclusions. The effect of liver injury on lamin nuclear IFs is unknown, though lamin mutations in several human diseases result in lamin disorganization and nuclear shape changes. We tested the hypothesis that lamins undergo aggregation during oxidative liver injury using two MDB mouse models: (i) mice fed the porphyrinogenic drug 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and (ii) mice that harbor a mutation in ferrochelatase (fch), which converts protoporphyrin IX to heme. Dramatic aggregation of lamin A/C and B1 was noted in the livers of both models in association with changes in lamin organization and nuclear shape, as determined by immunostaining and electron microscopy. The lamin aggregates sequester other nuclear proteins including transcription factors and ribosomal and nuclear pore components into high molecular weight complexes, as determined by mass-spectrometry and confirmed biochemically. Lamin aggregate formation is rapid and precedes keratin aggregation in fch livers, and is seen in liver explants of patients with alcoholic cirrhosis. Exposure of cultured cells to DDC, protoporphyrin IX or N-methyl-protoporphyrin, or incubation of purified lamins with protoporphyrin IX, also results in lamin aggregation. In contrast, lamin aggregation is ameliorated by TG2 inhibition. Therefore, lamin aggregation is an early sensor of porphyria-associated liver injury and might serve to buffer oxidative stress. The nuclear shape and lamin defects associated with porphyria phenocopy the changes seen in laminopathies and could result in transcriptional alterations due to sequestration of nuclear proteins.
authors: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Amika
authors: A
authors: Singla
authors: Nicholas W
authors: NW
authors: Griggs
authors: Raymond
authors: R
authors: Kwan
authors: Natasha T
authors: NT
authors: Snider
authors: Dhiman
authors: D
authors: Maitra
authors: Stephen A
authors: SA
authors: Ernst
authors: Harald
authors: H
authors: Herrmann
authors: M Bishr
authors: MB
authors: Omary
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D005294:Ferrochelatase / Q000235:genetics; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors; D056945:Hep G2 Cells; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism*; D034921:Lamin Type B / Q000378:metabolism*; D059609:Mallory Bodies / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress; D017094:Porphyrias, Hepatic / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D055503:Protein Multimerization / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011524:Protoporphyrins / Q000494:pharmacology; D011725:Pyridines / Q000633:toxicity; D011503:Transglutaminases / Q000037:antagonists & inhibitors
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; C494847:LMNA protein, human; D034904:Lamin Type A; D034921:Lamin Type B; D011524:Protoporphyrins; D011725:Pyridines; C028025:protoporphyrin IX; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D005294:Ferrochelatase
keywords: Lamin aggregation; Liver injury; Mallory-Denk bodies; Porphyria
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