ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Fat accumulation "sensitizes" the liver to insult and leads to nonalcoholic steatohepatitis (NASH). G protein-coupled receptor 35 (GPR35) is involved in metabolic stresses, but its role in NAFLD is unknown. We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis. Specifically, we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis, whereas loss of GPR35 had the opposite effect. Administration of the GPR35 agonist kynurenic acid (Kyna) suppressed HFCF diet-induced steatohepatitis in mice. Kyna/GPR35 induced expression of StAR-related lipid transfer protein 4 (STARD4) through the ERK1/2 signaling pathway, ultimately resulting in hepatic cholesterol esterification and bile acid synthesis (BAS). The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1, promoting the conversion of cholesterol to bile acid. The protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown mice. STARD4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in mice. Our findings indicate that the GPR35-STARD4 axis is a promising therapeutic target for NAFLD.
ABSTRACT
AIM To investigate the effects of berberine-evodiamine compatibility on expressions of intestinal acyl-CoA:cholesterol acyltransferase 2 (ACAT2),apolipoprotein B48 (ApoB48),and Niemann-Pick C1 Like 1 (NPC1L1) proteins in hypercholesterolemic rats.METHODS Fifty SD rats were assigned to control and model groups.After establishing the hypercholesterolemic rat model by feeding high fat and high cholesterol food,forty SD rats were equally divided into model control group,atorvastatin group,berberine-evodiamine compatibility groups (89.2 mg/kg,178.4 mg/kg).After four weeks treatment,serum triglycerides (TG),total cholesterol (TC),low-density lipoprotein cholesterol (LDL-C),high density lipoprotein cholesterol (HDL-C) were detected.Then the contents of cholesterol and β-sitoesterol in serum were determined by GC.The expressions of ACAT2,ApoB48 and NPC1 L1 proteins in the small intestine were assayed with immunohistochemistry technology.RESULTS Serum TC,TG and liver TC were significantly decreased in 89.2 mg/kg and 178.4 mg/kg berberineevodiamine compatibility groups compared with those in the model control group (P ＜ 0.01).Serum LDL-C and liver TC were also significantly decreased in 89.2 mg/kg berberine-evodiamine compatibility group (P ＜ 0.05).GC analysis indicated that the amount of cholesterol level and β-sitoesterol in serum were decreased in 178.4 mg/kg berberine-evodiamine compatibility group (P ＜ 0.05) and 89.2 mg/kg berberine-evodiamine compatibility group (P ＜ 0.01).Immunohistochemistry analysis manifested that the average luminous density of ACAT2,ApoB48 and NPC1L1 proteins in two dosages of berberine-evodiamine compatibility group were descended markedly compared with those in the model control group (P ＜ 0.05 or P ＜ 0.01).CONCLUSION The mechanisms underlying the cholesterol metabolism activity of berberine-evodiamine compatibility are mediated most likely by down-regulating the expressions of intestinal ACAT2,ApoB48 and NPC1 L1 proteins in hypercholesterolemic rats.
ABSTRACT
AIM To investigate the effects of berberine-evodiamine compatibility on expressions of intestinal acyl-CoA:cholesterol acyltransferase 2 (ACAT2),apolipoprotein B48 (ApoB48),and Niemann-Pick C1 Like 1 (NPC1L1) proteins in hypercholesterolemic rats.METHODS Fifty SD rats were assigned to control and model groups.After establishing the hypercholesterolemic rat model by feeding high fat and high cholesterol food,forty SD rats were equally divided into model control group,atorvastatin group,berberine-evodiamine compatibility groups (89.2 mg/kg,178.4 mg/kg).After four weeks treatment,serum triglycerides (TG),total cholesterol (TC),low-density lipoprotein cholesterol (LDL-C),high density lipoprotein cholesterol (HDL-C) were detected.Then the contents of cholesterol and β-sitoesterol in serum were determined by GC.The expressions of ACAT2,ApoB48 and NPC1 L1 proteins in the small intestine were assayed with immunohistochemistry technology.RESULTS Serum TC,TG and liver TC were significantly decreased in 89.2 mg/kg and 178.4 mg/kg berberineevodiamine compatibility groups compared with those in the model control group (P ＜ 0.01).Serum LDL-C and liver TC were also significantly decreased in 89.2 mg/kg berberine-evodiamine compatibility group (P ＜ 0.05).GC analysis indicated that the amount of cholesterol level and β-sitoesterol in serum were decreased in 178.4 mg/kg berberine-evodiamine compatibility group (P ＜ 0.05) and 89.2 mg/kg berberine-evodiamine compatibility group (P ＜ 0.01).Immunohistochemistry analysis manifested that the average luminous density of ACAT2,ApoB48 and NPC1L1 proteins in two dosages of berberine-evodiamine compatibility group were descended markedly compared with those in the model control group (P ＜ 0.05 or P ＜ 0.01).CONCLUSION The mechanisms underlying the cholesterol metabolism activity of berberine-evodiamine compatibility are mediated most likely by down-regulating the expressions of intestinal ACAT2,ApoB48 and NPC1 L1 proteins in hypercholesterolemic rats.
ABSTRACT
Several proteins are involved in the absorption of cholesterol in small intestine.Niemann-Pick C1 like 1 (NPC1L1) mainly mediates the absorption of cholesterol, and acyl-coenzyme A ( CoA)∶cholesterol acyltransferase 2 (ACAT2) catalyzes the free cholesterol absorpted by intestine into cholesterol ester,while unesterified free cholesterol is secreted into intestinal lumen by ATP-binding cassette(ABC) transporters G5/G8(ABCG5/ABCG8).Transcription factor liver X receptor( LXR) plays an important role in the process of intestinal cholesterol absorption.The research progress in NPC1L1,ABCG5/ABCG8,ACAT2 and LXR is reviewed in this article.