BACKGROUND The global prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has continued to increase annually.Recent studies have indicated that inhibition of metabotropic glutamate receptor 5(...BACKGROUND The global prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has continued to increase annually.Recent studies have indicated that inhibition of metabotropic glutamate receptor 5(mGluR5)may alleviate hepatic steatosis.However,the precise mechanism warrants further exploration.AIM To investigate the potential mechanism by which mGluR5 attenuates hepatocyte steatosis in vitro and in vivo.METHODS Free fatty acids(FFAs)-stimulated HepG2 cells were treated with the mGluR5 antagonist MPEP and the mGluR5 agonist CHPG.Oil Red O staining and a triglyceride assay kit were used to evaluate lipid content.Western blot analysis was conducted to detect the expression of the autophagy-associated proteins p62 and LC3-II,as well as the expression of the key signaling molecules AMPK and ULK1,in the treated cells.To further elucidate the contributions of autophagy and AMPK,we used chloroquine(CQ)to inhibit autophagy and compound C(CC)to inhibit AMPK activity.In parallel,wild-type mice and mGluR5 knockout(KO)mice fed a normal chow diet or a high-fat diet(HFD)were used to evaluate the effect of mGluR5 inhibition in vivo.RESULTS mGluR5 inhibition by MPEP attenuated hepatocellular steatosis and increased LC3-II and p62 protein expression.The autophagy inhibitor CQ reversed the effects of MPEP.In addition,MPEP promoted AMPK and ULK1 expression in HepG2 cells exposed to FFAs.MPEP treatment led to the nuclear translocation of transcription factor EB,which is known to promote p62 expression.This effect was negated by the AMPK inhibitor CC.mGluR5 KO mice presented reduced body weight,improved glucose tolerance and reduced hyperlipidemia when fed a HFD.Additionally,the livers of HFD-fed mGluR5 KO mice presented increases in LC3-II and p62.CONCLUSION Our results suggest that mGluR5 inhibition promoted autophagy and reduced hepatocyte steatosis through activation of the AMPK signaling pathway.These findings reveal a new functional mechanism of mGluR5 as a target in the treatment of MASLD.展开更多
BACKGROUND Maturity-onset diabetes of the young(MODY)is a monogenic genetic disease often clinically misdiagnosed as type 1 or type 2 diabetes.MODY type 9(MODY9)is a rare subtype caused by mutations in the PAX4 gene.C...BACKGROUND Maturity-onset diabetes of the young(MODY)is a monogenic genetic disease often clinically misdiagnosed as type 1 or type 2 diabetes.MODY type 9(MODY9)is a rare subtype caused by mutations in the PAX4 gene.Currently,there are limited reports on PAX4-MODY,and its clinical characteristics and treatments are still unclear.In this report,we described a Chinese patient with high autoimmune antibodies,hyperglycemia and a site mutation in the PAX4 gene.CASE SUMMARY A 42-year-old obese woman suffered diabetes ketoacidosis after consuming substantial amounts of beverages.She had never had diabetes before,and no one in her family had it.However,her autoantibody tested positive,and she managed her blood glucose within the normal range for 6 mo through lifestyle interventions.Later,her blood glucose gradually increased.Next-generation sequencing and Sanger sequencing were performed on her family.The results revealed that she and her mother had a heterozygous mutation in the PAX4 gene(c.314G>A,p.R105H),but her daughter did not.The patient is currently taking liraglutide(1.8 mg/d),and her blood glucose levels are under control.Previous cases were retrieved from PubMed to investigate the relationship between PAX4 gene mutations and diabetes.CONCLUSION We reported the first case of a PAX4 gene heterozygous mutation site(c.314G>A,p.R105H),which does not appear pathogenic to MODY9 but may facilitate the progression of latent autoimmune diabetes in adults.展开更多
基金Supported by National Natural Science Foundation of China,No.81800771 and No.81300702.
文摘BACKGROUND The global prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has continued to increase annually.Recent studies have indicated that inhibition of metabotropic glutamate receptor 5(mGluR5)may alleviate hepatic steatosis.However,the precise mechanism warrants further exploration.AIM To investigate the potential mechanism by which mGluR5 attenuates hepatocyte steatosis in vitro and in vivo.METHODS Free fatty acids(FFAs)-stimulated HepG2 cells were treated with the mGluR5 antagonist MPEP and the mGluR5 agonist CHPG.Oil Red O staining and a triglyceride assay kit were used to evaluate lipid content.Western blot analysis was conducted to detect the expression of the autophagy-associated proteins p62 and LC3-II,as well as the expression of the key signaling molecules AMPK and ULK1,in the treated cells.To further elucidate the contributions of autophagy and AMPK,we used chloroquine(CQ)to inhibit autophagy and compound C(CC)to inhibit AMPK activity.In parallel,wild-type mice and mGluR5 knockout(KO)mice fed a normal chow diet or a high-fat diet(HFD)were used to evaluate the effect of mGluR5 inhibition in vivo.RESULTS mGluR5 inhibition by MPEP attenuated hepatocellular steatosis and increased LC3-II and p62 protein expression.The autophagy inhibitor CQ reversed the effects of MPEP.In addition,MPEP promoted AMPK and ULK1 expression in HepG2 cells exposed to FFAs.MPEP treatment led to the nuclear translocation of transcription factor EB,which is known to promote p62 expression.This effect was negated by the AMPK inhibitor CC.mGluR5 KO mice presented reduced body weight,improved glucose tolerance and reduced hyperlipidemia when fed a HFD.Additionally,the livers of HFD-fed mGluR5 KO mice presented increases in LC3-II and p62.CONCLUSION Our results suggest that mGluR5 inhibition promoted autophagy and reduced hepatocyte steatosis through activation of the AMPK signaling pathway.These findings reveal a new functional mechanism of mGluR5 as a target in the treatment of MASLD.
基金Supported by the National Natural Science Foundation of China,No.81300702the Natural Science Foundation Project of Chongqing CSTC,No.cstc2018jcyjAXO210.
文摘BACKGROUND Maturity-onset diabetes of the young(MODY)is a monogenic genetic disease often clinically misdiagnosed as type 1 or type 2 diabetes.MODY type 9(MODY9)is a rare subtype caused by mutations in the PAX4 gene.Currently,there are limited reports on PAX4-MODY,and its clinical characteristics and treatments are still unclear.In this report,we described a Chinese patient with high autoimmune antibodies,hyperglycemia and a site mutation in the PAX4 gene.CASE SUMMARY A 42-year-old obese woman suffered diabetes ketoacidosis after consuming substantial amounts of beverages.She had never had diabetes before,and no one in her family had it.However,her autoantibody tested positive,and she managed her blood glucose within the normal range for 6 mo through lifestyle interventions.Later,her blood glucose gradually increased.Next-generation sequencing and Sanger sequencing were performed on her family.The results revealed that she and her mother had a heterozygous mutation in the PAX4 gene(c.314G>A,p.R105H),but her daughter did not.The patient is currently taking liraglutide(1.8 mg/d),and her blood glucose levels are under control.Previous cases were retrieved from PubMed to investigate the relationship between PAX4 gene mutations and diabetes.CONCLUSION We reported the first case of a PAX4 gene heterozygous mutation site(c.314G>A,p.R105H),which does not appear pathogenic to MODY9 but may facilitate the progression of latent autoimmune diabetes in adults.
