Serum matrix metalloproteinase-1 level represents disease activity as opposed to fibrosis in patients with histologically proven nonalcoholic steatohepatitis

BACKGROUND/AIMS: Nonalcoholic steatohepatitis (NASH) is prevalent in both economically developed and developing countries. Twenty percent of NASH progresses to cirrhosis with/without hepatocellular carcinoma, and there is an urgent need to find biomarkers for early diagnosis and monitoring progression of the disease. Using immunohistochemical and immunoelectron microscopic examination we previously reported that expression of matrix metalloproteinase-1 (MMP-1) increased in monocytes, Kupffer cells and hepatic stellate cells in early stage NASH. The present study investigated whether serum MMP-1 levels reflect disease activity and pharmaceutical effects in NASH patients. METHODS: We measured the serum levels of MMPs, tissue inhibitors of metalloproteinases (TIMPs), and several cytokines/chemokines in patients with histologically proven early and advanced stages of NASH and compared them with those in healthy controls. RESULTS: Serum MMP-1 levels in stage 1 fibrosis, but not in the more advanced fibrosis stages, were significantly higher than in healthy controls (P=0.019). There was no correlation between serum MMP-1 level and fibrosis stage. Serum MMP- 1 levels in NASH patients represented disease activity estimated by serum aminotransferase values during the follow-up period. In contrast, MMP-2, MMP-9 and TIMPs did not change with disease activity. Consistent with the finding that MMP-1 is expressed predominantly in monocytes and Kupffer cells, serum levels of monocyte chemotactic protein-1 and granulocyte-colony stimulating factor were significantly increased in NASH with stage 1 fibrosis. CONCLUSIONS: These results suggest that serum MMP-1 levels represent disease activity and may serve as a potential biomarker for monitoring the progression of NASH.

The Use of Docosahexaenoic Acid Supplementation to Ameliorate the Hyperactivity of Rat Pups Induced by in utero Ethanol Exposure

It has been demonstrated that in utero ethanol(EtOH) exposure induces hyperactive behavior and learning disturbances in offspring. In order to investigate the effects of docosahexaenoic acid(DHA) on these neurobehavioral dysfunctions of rat pups induced by in utero EtOH exposure, pregnant Wistar rats were divided into four treatment groups depending on the type of oil added to the diet and drinking water as follows; (a)5% safflower oil with tap water(TW/n−6), (b)3% safflower oil and 2% DHA with tap water(TW/n−3), (c)5% safflower oil with 10%−EtOH(ET/n−6), (d)3% safflower oil and 2% DHA with 10%−EtOH(ET/n−3) at gestational day (GD)7. 10%−EtOH was administered to dams in ET/n−6 and ET/n−3 groups from GD 7 to the pups’ weaning(postnatal week 4), and all pups were fed with the same diet that was given to their dams during the entire examination period. The open−field test and the water E−maze test were conducted for all pups, and a spontaneous motor activity test and the Sidman electric shock avoidance test were performed for some of male pups. Amounts of monoamine metabolites in striatum were then determined, and fatty acid analyses of total brain lipids were performed. The male pups in the ET/n−6 group showed significantly more rearing and square−crossing movements in the open−field test, and significanrly higher spontaneous motor activity during the dark period in the daily cycle compared to the males in the TW/n−6 group. The male pups in the ET/n−3 group showed fewer of these behaviors in the open−field test compared to the ET/n−6 group males, and a normal pattern of spontaneous motor activity. Learning disturbance induced by in utero EtOH exposure was not observed in the E−shaped water maze, but was observed in the avoidance rates in the Sidman electric shock avoidance test. However, there was no significant modifying effect of DHA on the avoidance rates in EtOH exposed pups. The analysis of the fatty acid composition of total lipids in the brains of the pups revealed high levels of DHA in the diet reflected an increased level of brain DHA and caused a decreased level of the brain arachidonic acid. Retroconversion from DHA to eicosapentaenoic acid was also observed. However, there was no significant effect of DHA on the levels of monoamine metabolites. These results support the hypothesis that DHA can counteract the attention deficit hyperactivity disorder.