ausblenden:
Schlagwörter:
ALT, alanine aminotransferase; AMP, adenosine monophosphate; AMPK, AMP-activated proteinkinase; ATP, adenosine triphosphate; ATP8, ATP synthase protein 8; Arg, arginine; Asp, aspartic acid; B6-mtB6, C57BL/6; B6-mtFVB, C57BL/6-mtFVB/N; C0, free dl-carnitine; C16, hexadecanoyl-l-carntine; C18, octadecanoyl-l-carnitine; CD, control diet; CD3, cluster of differentiation receptor 3; CPT I, carnitine-palmitoyltransferase I; CYP51A1, cytochrome P450, family 51, subfamily A, polypeptide 1; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; Gr1, granulocyte differentiation antigen 1; H&E, hematoxylin–eosin staining; H2O2, hydrogen peroxide; Hsd17b7, 17-beta-hydroxysteroid dehydrogenase type 7; IDI1, isopentenyl-diphosphate delta isomerase 1; IL, interleukin; IPA, ingenuity pathway analysis; KEGG, Kyoto Encyclopedia of Genes and Genomes; Lipid metabolism; Ly6G, lymphocyte antigen 6 complex, locus G; MCDD, methionine and choline deficient diet; MSMO1, methylsterol monooxygenase 1; Met, methionine; Mitochondrial dysfunction; Mitochondrial gene polymorphism; NAFL, non-alcoholic liver steatosis; NAFLD; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, non-alcoholic steatohepatitis; ND3, NADH dehydrogenase subunit 3; OCR, oxygen consumption rate; OXPHOS, oxidative phosphorylation system; PBS, phosphate buffered saline; ROS, reactive oxygen species; SNPs, single nucleotide polymorphisms; SOD2, superoxide dismutase 2; STRING, Search Tool for the Retrieval of Interacting Genes/Proteins; Steatohepatitis; TNFα; TNFα, tumor necrosis factor alpha; Tyr, tyrosine; WD, western-style diet; mt, mitochondrial; pAMPK, phosphorylated AMP-activated proteinkinase
Zusammenfassung:
OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with an enhanced risk for liver and cardiovascular diseases and mortality. NAFLD can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH). However, the mechanisms predisposing to this progression remain undefined. Notably, hepatic mitochondrial dysfunction is a common finding in patients with NASH. Due to a lack of appropriate experimental animal models, it has not been evaluated whether this mitochondrial dysfunction plays a causative role for the development of NASH. METHODS: To determine the effect of a well-defined mitochondrial dysfunction on liver physiology at baseline and during dietary challenge, C57BL/6J-mt(FVB/N) mice were employed. This conplastic inbred strain has been previously reported to exhibit decreased mitochondrial respiration likely linked to a non-synonymous gene variation (nt7778 G/T) of the mitochondrial ATP synthase protein 8 (mt-ATP8). RESULTS: At baseline conditions, C57BL/6J-mt(FVB/N) mice displayed hepatic mitochondrial dysfunction characterized by decreased ATP production and increased formation of reactive oxygen species (ROS). Moreover, genes affecting lipid metabolism were differentially expressed, hepatic triglyceride and cholesterol levels were changed in these animals, and various acyl-carnitines were altered, pointing towards an impaired mitochondrial carnitine shuttle. However, over a period of twelve months, no spontaneous hepatic steatosis or inflammation was observed. On the other hand, upon dietary challenge with either a methionine and choline deficient diet or a western-style diet, C57BL/6J-mt(FVB/N) mice developed aggravated steatohepatitis as characterized by lipid accumulation, ballooning of hepatocytes and infiltration of immune cells. CONCLUSIONS: We observed distinct metabolic alterations in mice with a mitochondrial polymorphism associated hepatic mitochondrial dysfunction. However, a second hit, such as dietary stress, was required to cause hepatic steatosis and inflammation. This study suggests a causative role of hepatic mitochondrial dysfunction in the development of experimental NASH.
