ABSTRACT
Left untreated, nonalcoholic fatty liver disease can progress to nonalcoholic steatohepatitis (NASH), fibrosis, and end-stage liver disease. To date, few if any therapies have proven effective against NASH with fibrosis. Quantification and qualification of hepatic scar might enable development of more effective targeted therapies. In a murine model of NASH induced by diet, we characterized fibrillar collagen deposition within the hepatic parenchyma. At harvest, livers from the modified diet cohort exhibited NASH with fibrosis. Transcriptomic analysis of hepatic tissue revealed increased col1a1, col1a2, and col3a1, each of which correlated directly with hepatic hydroxyproline content. Circular polarized microscopic analysis of Picrosirius red-stained liver sections revealed deposition of collagen type I within the parenchyma. Development of therapeutics designed to mitigate collagen type I accumulation might prove effective in NASH with fibrosis.
Subject(s)
Collagen Type III/genetics , Collagen Type I/genetics , Collagen/metabolism , Fast Foods/adverse effects , Non-alcoholic Fatty Liver Disease/metabolism , Animals , Case-Control Studies , Collagen/genetics , Collagen Type I, alpha 1 Chain , Disease Models, Animal , Female , Gene Expression Profiling , Gene Expression Regulation/drug effects , Liver/drug effects , Liver/metabolism , Male , Mice , Microscopy, Polarization , Non-alcoholic Fatty Liver Disease/chemically induced , Non-alcoholic Fatty Liver Disease/genetics , Up-RegulationABSTRACT
There is increasing evidence that nonalcoholic steatohepatitis (NASH) is a risk factor for hepatocellular carcinoma (HCC) in the absence of cirrhosis, a phenomenon termed noncirrhotic HCC. Early diagnosis of HCC is critical to a favorable prognosis. We tested the hypothesis that hydroxyproline content of liver biopsy samples is diagnostic for HCC in murine models of NASH induced by diet or by diet and chemicals. The training set comprised mice fed a standard diet or a fast-food diet with or without administration of thioacetamide. At harvest, livers from the modified diet cohort exhibited NASH with a subset of NASH livers exhibiting HCC. Hydroxyproline content was measured in liver biopsy samples with tissue in the NASH+HCC cohort sampled from the remote, nontumor parenchyma. Plotting the receiver operating characteristics (ROC) with hydroxyproline as the continuous variable against the absence or presence of HCC yielded an area under ROC of 0.87, a threshold of >0.18 µg hydroxyproline/mg liver and sensitivity of 91% with a specificity of 83.3%. The use of liver hydroxyproline content as a diagnostic for HCC in a test set comprising healthy, NASH and NASH+HCC livers proved 87% accurate.
