Cajanonic Acid Alleviates Liver Injury of Nonalcoholic Fatty Liver Disease in db/db Mice
Objective Nonalcoholic fatty liver disease(NAFLD)is a condition in which excess fat accumulates in the liver.It is closely associated with metabolic syndromes such as obesity,insulin resistance,type-2 diabetes mellitus(T2DM),and dyslipidemia.Liver fibrosis is a key process in the further development of NAFLD into hepatocellular carcinoma(HCC).Therefore,reducing the accumulation of fat in the liver is crucial in slowing or stopping the progression of NAFLD to fibrosis and treating the condition.Cajanonic Acid A(CAA)effectively improves insulin resistance and has glucose-reducing and lipid-lowering effects in type 2 diabetes mellitus.The objective of this study was to examine the protective effect of CAA against liver injury in NAFLD.The db/db spontaneous NAFLD mouse was used and divided into two groups:the NAFLD group and the CAA administration group.The CAA group was administered 50 mg/(kg·d)of CAA by gavage.During the same period,C57BL mice were used as the normal control group(NC group),with six mice in each group.Biochemical index tests and histopathological staining in mice revealed that CAA intervention effectively alleviated glucose-lipid metabolism disorders,hepatic function impairment(P＜0.05),hepatic steatosis,and reduced lipid deposition in db/db mice(P＜0.05).The level of interleukin 1β(IL-1β)in the supernatant of liver tissues was significantly reduced after CAA treatment(P＜0.05).The results indicate that CAA has a significant anti-inflammatory effect.Additionally,the intervention of CAA led to a significant attenuation of fibrosis in the mouse liver.Sirius red staining revealed a significant reduction in collagen deposition in the CAA group(P＜0.05).Western blotting results show a decrease in the protein expression of fibronectin and α-smooth muscle actin(α-SMA),genes related to fibrosis,and an increase in the expression of E-cadherin in the CAA group(P＜0.05).Previous studies have identified E2F transcription factor 1(E2F1)as a key factor in glucose and liver lipid metabolism,with increased expression in obese mice.It may also be involved in adipose tissue metabolism through transcriptional regulation of PPARγ.Our hypothesis is that E2F1 serves as an intermediate target of CAA to improve hepatic lipid deposition and fibrosis in NAFLD.Immunohistochemical staining revealed the expression of E2F1 and its homologous antagonist,E2F transcription factor 7(E2F7),in the nucleus pulposus of liver tissues of mice treated with CAA.The protein and mRNA expression levels were further detected by Western blotting and real-time fluorescence quantitative PCR.The results showed a decrease in the protein and mRNA expression level of E2F1(P＜0.05)and an increase in E2F7(P＜0.05)in CAA group compared to the NAFLD group.Spearman rank correlation analysis indicated a significant negative correlation(P＜0.05)between E2F1 and E2F7.The results indicated that CAA can effectively improve glucose-lipid metabolism disorder in db/db mice with NAFLD.It can also inhibit lipid overdeposition and attenuate hepatic fibrosis to alleviate the further progression of NAFLD.Additionally,it is possible that E2F1 and E2F7 are involved in the process of CAA to improve lipid metabolism and fibrosis.
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