出版社：American Society for Biochemistry and Molecular Biology
摘要：Methionine-choline-deficient (MCD) diets that cause steatohepatitisin rodents are typically enriched in polyunsaturated fat. Todetermine whether the fat composition of the MCD formula influencesthe development of liver disease, we manufactured custom MCDformulas with fats ranging in PUFA content from 2% to 59% andtested them for their ability to induce steatohepatitis. Allmodified-fat MCD formulas caused identical degrees of hepaticsteatosis and resulted in a similar distribution of fat withinindividual hepatic lipid compartments. The fatty acid compositionof hepatic lipids, however, reflected the fat composition ofthe diet. Mice fed a PUFA-rich MCD formula showed extensivehepatic lipid peroxidation, induction of proinflammatory genes,and histologic inflammation. When PUFAs were substituted withmore saturated fats, lipid peroxidation, proinflammatory geneinduction, and hepatic inflammation all declined significantly.Despite the close relationship between PUFAs and hepatic inflammationin mice fed MCD formulas, dietary fat had no impact on MCD-mediateddamage to hepatocytes. Indeed, histologic apoptosis and serumalanine aminotransferase levels were comparable in all MCD-fedmice regardless of dietary fat content. Together, these resultsindicate that dietary PUFAs promote hepatic inflammation butnot hepatotoxicity in the MCD model of liver disease. Thesefindings emphasize that individual dietary nutrients can makespecific contributions to steatohepatitis.Supplementary key words steatohepatitis • fatty liver • lipotoxicity • inflammation • apoptosis
Abbreviations: ALT, alanine aminotransferase; COX-2, cyclooxygenase-2; CXCL-2, CXC chemokine ligand-2; CYP2E1, cytochrome P4502E1; I-kB, inhibitor of NF-B; iNOS, inducible nitric oxide synthase; MCD, methionine-choline-deficient; MCS, methionine-choline-sufficient; MTP, microsomal triglyceride transfer protein; NF-B, nuclear factor-B; PL, phospholipid; SFA, saturated fatty acid; TAG, triacylglycerol; TBARS, thiobarbituric acid-reactive substances; TNF, tumor necrosis factor; TUNEL, terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling
B; iNOS, inducible nitric oxide synthase; MCD, methionine-choline-deficient; MCS, methionine-choline-sufficient; MTP, microsomal triglyceride transfer protein; NF-
