Abstract
Our aim was to test whether pharmacological inhibition of cycloxygenase-2 (COX-2) reverses non-alcoholic steatohepatitis (NASH) in type 2 diabetes mellitus (T2DM) rats via suppression of the non-canonical Wnt signaling pathway expression. Twenty-four male Sprague-Dawley rats were randomly distributed to two groups and were fed with a high fat and sucrose (HF-HS) diet or a normal chow diet, respectively. After four weeks, rats fed with a HF-HS diet were made diabetic with low-dose streptozotocin. At the 9th week the diabetic rats fed with a HF-HS diet or the non-diabetic rats fed with a normal chow diet were further divided into two subgroups treated with vehicle or celecoxib (a selective COX-2 inhibitor, 10 mg/Kg/day, gavage) for the last 4 weeks, respectively. At the end of the 12th week, rats were anesthetized. NASH was assessed by histology. Related cytokine expression was measured at both the protein and gene levels through immunohistochemistry (IHC), Western blot and real-time PCR. T2DM rats fed with a HF-HS diet developed steatohepatitis and insulin resistance associated with elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), insulin levels and the non-alcoholic fatty liver disease (NAFLD) activity score (NAS). The expression of Wnt5a, JNK1, NF-κB p65, and COX-2 were all significantly increased in the T2DM-NASH group compared with the control and control-cele group. Hepatic injury was improved by celecoxib in T2DM-NASH-Cele group indicated by reduced serum ALT and AST levels and hepatic inflammation was reduced by celecoxib showed by histology and the NAFLD activity score (NAS). Serum related metabolic parameters, HOMA-IR and insulin sensitivity index were all improved by celecoxib. The expression of Wnt5a, JNK1, NF-κB p65, and COX-2 expression were all suppressed by celecoxib in T2DM-NASH-Cele group. The results of the present study indicated that celecoxib ameliorated NASH in T2DM rats via suppression of the non-canonical Wnt5a/JNK1 signaling pathway expression.
Highlights
Non-alcoholic steatohepatitis (NASH) is one of the most frequent causes of abnormal liver function and correlates with central adiposity, insulin resistance, dyslipidemia, and type 2 diabetes mellitus (T2DM) [1]
Rats fed with a HF-HS diet showed significantly lower body weight (BW); but higher liver weight index than rats fed with a chow diet (CHOW) diet (Table 1)
No significant difference between the T2DM-NASH group and T2DM-NASH-Cele group was found in BW and liver weights, the liver weight index did make a difference (Table 1)
Summary
Non-alcoholic steatohepatitis (NASH) is one of the most frequent causes of abnormal liver function and correlates with central adiposity, insulin resistance, dyslipidemia, and T2DM [1]. T2DM might be an independent risk factor for the progression of non-alcoholic fatty liver disease (NAFLD) from simple steatosis to NASH and fibrosis [3,4]. The mechanisms by which diabetes aggravates the progression of NASH mainly include insulin resistance, insulin deficiency, inflammatory response, and oxidative stress mediated by cytokines and chemokines [4,5]. COX-2 inhibitors reduced COX-2 expression by inhibiting NF-kB expression and activation [10] Despite of these studies, there was hardly any research which indicated the role of COX-2 in the diabetic model of NASH and whether inhibiting COX-2 reversed diabetes-related NASH
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