Lenvatinib is widely used as a first-line chemotherapy for advanced hepatocellular carcinoma(HCC),a highly metastatic and recurrent cancer.However,HCC cells often develop resistance to lenvatinib,thus reducing its eff...Lenvatinib is widely used as a first-line chemotherapy for advanced hepatocellular carcinoma(HCC),a highly metastatic and recurrent cancer.However,HCC cells often develop resistance to lenvatinib,thus reducing its efficacy.This study aims to investigate the impact of STARD4,a crucial cholesterol transporter,on HCC growth and lenvatinib resistance,as well as explore the involvement of the EGFR/PI3K/AKT signaling pathway in STARD4's role.Analysis of clinical samples from HCC patients revealed increased expression of both STARD4 and EGFR in tumor tissues,with a strong correlation between STARD4 expression and malignancy progression.In vitro and in vivo studies demonstrated that STARD4 promoted HCC growth and hindered lenvatinib's anti-tumor effect,while STARD4 down-regulation exerted opposite effects.Further investigation revealed that depletion of STARD4 increased cholesterol accumulation in the plasma membrane,resulting in reduced EGFR phosphorylation.Moreover,cholesterol depletion attenuated these effects,suggesting STARD4 activates EGFR/PI3K/AKT signaling in a cholesterol-dependent manner.To elucidate the underlying mechanism of lenvatinib resistance,we established the lenvatinib-resistant HCC cell lines and found increased stimulation of both STARD4 and EGFR signaling.Furthermore,the EGFR inhibitor erlotinib suppressed the promotion of HCC progression by STARD4,reinforcing its role in activating the EGFR/PI3K/AKT pathway.In conclusion,this study demonstrates that STARD4 enhances HCC growth and lenvatinib resistance by regulating cholesterol homeostasis and activating the EGFR/PI3K/AKT pathway.These findings suggest STARD4 as a potential molecular biomarker for predicting lenvatinib resistance and as a therapeutic target in HCC treatment.展开更多
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...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.展开更多
基金supported by the Guangdong Basic and Applied Basic Research Foundation of China(No.2023A1515012595,2024A1515012743)Nanfang Hospital Dean's Fund(No.2022A010)+1 种基金Wu Jieping Medical Foundation(No.320.6750.2023-06-18)Hospital Pharmacy Research Foundation of the Guangdong Liver Disease Association of China(No.2023gdsgzbzd01).
文摘Lenvatinib is widely used as a first-line chemotherapy for advanced hepatocellular carcinoma(HCC),a highly metastatic and recurrent cancer.However,HCC cells often develop resistance to lenvatinib,thus reducing its efficacy.This study aims to investigate the impact of STARD4,a crucial cholesterol transporter,on HCC growth and lenvatinib resistance,as well as explore the involvement of the EGFR/PI3K/AKT signaling pathway in STARD4's role.Analysis of clinical samples from HCC patients revealed increased expression of both STARD4 and EGFR in tumor tissues,with a strong correlation between STARD4 expression and malignancy progression.In vitro and in vivo studies demonstrated that STARD4 promoted HCC growth and hindered lenvatinib's anti-tumor effect,while STARD4 down-regulation exerted opposite effects.Further investigation revealed that depletion of STARD4 increased cholesterol accumulation in the plasma membrane,resulting in reduced EGFR phosphorylation.Moreover,cholesterol depletion attenuated these effects,suggesting STARD4 activates EGFR/PI3K/AKT signaling in a cholesterol-dependent manner.To elucidate the underlying mechanism of lenvatinib resistance,we established the lenvatinib-resistant HCC cell lines and found increased stimulation of both STARD4 and EGFR signaling.Furthermore,the EGFR inhibitor erlotinib suppressed the promotion of HCC progression by STARD4,reinforcing its role in activating the EGFR/PI3K/AKT pathway.In conclusion,this study demonstrates that STARD4 enhances HCC growth and lenvatinib resistance by regulating cholesterol homeostasis and activating the EGFR/PI3K/AKT pathway.These findings suggest STARD4 as a potential molecular biomarker for predicting lenvatinib resistance and as a therapeutic target in HCC treatment.
基金supported by the National Science Fund for Distinguished Young Scholars(#82225008,China)the National Natural Science Foundation of China(#82070608)+1 种基金the Anhui Provincial Natural Science Foundation(#2108085Y28,China)the Research Improvement Program of Anhui Medical University(#2019xkjT007,China).
文摘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.
