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  • br Materials and methods br Results

    2021-09-22


    Materials and methods
    Results
    Discussion Previously, it is well known that methionine and choline deficient (MCDD) or choline-deficient, L-amino acid-defined (CDAA) models are widely accepted in NASH research. MCDD or CDAA dietary model has been mimic human NASH in rodents by sequentially producing steatohepatitis, liver fibrosis and liver cancer (Kashireddy and Rao, 2004; Rizki et al., 2006; Nakae et al., 1990). The mechanism of these dietary model mice are thought that lipid export from the liver to peripheral tissues may be impaired due to defective incorporation of triglycerides into apolipoprotein B (ApoB) or reduced ApoB synthesis or excretion. However, there was major problem that MDD or CDAA fed mice show severe loss of body weight. In this study, a CDAHF diet consisting of 60kcal% fat and 0.1% methionine was selected because CDAHF produces a more progressive liver pathology characterized by the development of steatosis with inflammation and fibrosis in rodent models within a short time, but not weight loss (Matsumoto et al., 2013). In our previous report, we have shown that mice fed CDAHF for 1 week induced increased plasma AST and ALT levels, fatty deposition and inflammatory cell infiltration (Harada et al., 2017). These mice did not show the hepatic fibrosis as shown in Supplementary data. On the other hand, mice fed CDAHF diet for 2 weeks showed more increased plasma AST and ALT levels, more bigger fatty deposition, higher inflammatory cell infiltration, and minimal fibrosis than that of mice fed CDAHF diet for 1 week. Therefore, in the present study, we used 2 weeks CDAHF feeding model because mice fed CDAHF diet for 2 weeks is enough to evaluate the mechanism underlying NASH progression. Furthermore, we found that this model could be easily to show the characteristic of NAFLD/NASH with slightly fibrosis which reflect the early statement of human NASH patient. Among current clinical studies of NAFLD/NASH, the results of many meta-analyses found that supplementation with n−3 fatty acids improves steatosis and steatohepatitis, but not fibrosis (Sanyal et al., 2014, Scorletti et al., 2014, Argo et al., 2015, Dasarathy et al., 2015). At the present time, there are growing evidences that n-3 supplementation may show the therapeutic effect in NAFLD. On the other hand, n−3 fatty HET0016 supplementation did not lead to an improvement in the primary outcome of histological activity in NASH patients (reduction of ≥ 2 points in NAFLD activity score) (Sanyal et al., 2014, Scorletti et al., 2014, Argo et al., 2015, Dasarathy et al., 2015). Therefore, further clinical trial and basic studies with longer treatment durations are warranted to assess the effectiveness of highly purified or increased intake of n−3 PUFA on NASH. In the basic research, there are several evidences regarding preventive effect of DHA on the development of NAFLD/NASH (Takayama et al., 2010, Lytle et al., 2015). DHA supplementation may attenuate the inflammatory response by lowering of the n−6 fatty acids ratio and decreasing oxidative stress, thereby effectively inhibiting liver fibrosis during NASH progression (Takayama et al., 2010). It is reported that DHA blocks progression of western diet-induced nonalcoholic steatohepatitis in obese Ldlr-/- mice (Lytle et al., 2017, Suzuki-Kemuriyama et al., 2016). However, it is unclear the mechanism how DHA prevent the progression of NAFLD/NASH in rodents. In this study, we found that GPR120KO mice did not show DHA-induced preventive effect of NASH, suggesting that DHA could be prevented the development of NAFLD/NASH via GPR120/FFAR4 signaling. Next, to clarify whether NASH progression is mediated through GPR120/FFAR4 signaling, we estimated the liver damages in GPR120KO mice fed CDAHF diet. We found that GPR120KO mice fed CDAHF diet induced increment of inflammatory response in the liver for 2 weeks feeding compared to WT mice fed CDAHF diet. Oh et al., demonstrated that GPR120 KO mice increased adipocyte-derived inflammatory response (Oh et al., 2010). These possible mechanisms are thought that GPR120/FFAR4 suppresses phospholiration of TAK-1 which associate with regulation of NF-κB signaling. Previously, pro- and anti-inflammatory cytokines production is involved in the macrophage M1 and M2 polarization, respectively. Raptis et al., showed that omega-3 may show the promotion of M2 polarization via GPR120/FFAR4 (Raptis et al., 2014), indicating that the deletion of GPR120/FFAR4 exacerbated inflammatory responses via increasing M1 macrophages. More resent study demonstrated that EPA shows anti-inflammatory effect via GPR120 in 3T3-L1 adipocytes or mice adipose tissue (Yamada et al., 2017). Based on previous data and our results, we suggest that GPR120KO mice may exacerbate inflammatory response in the liver via increasing the phenotype of M1 macrophage or may increase the phospholiration of TAK-1 in white adipose tissue. Thus, these results suggest that the deletion of GPR120/FFAR4 may exacerbate inflammatory response in the liver of mice fed CDAHF diet for 2 weeks. However, at present, we cannot explain the mechanism underlying the deletion of GPR120/FFAR4 progress the inflammatory response of NASH.