Nonalcoholic fatty liver disease or nonalcoholic fatty liver disease(NAFLD) refers to a group of disorders that arise from the accrual of fat in hepatocytes. Although various factors have been associated with the deve...Nonalcoholic fatty liver disease or nonalcoholic fatty liver disease(NAFLD) refers to a group of disorders that arise from the accrual of fat in hepatocytes. Although various factors have been associated with the development of NAFLD, including genetic predisposition and environmental exposures, little is known aboutthe underlying pathogenesis of the disease. Research efforts are ongoing to identify biological targets and signaling pathways that mediate NAFLD. Emerging evidence has implicated a role for micro RNAs(mi RNAs), short single-stranded molecules that regulate gene expression either transcriptionally, through targeting of promoter regions, or post-transcriptionally, by blocking translation or promoting cleavage of specific target m RNAs. Several mi RNAs have been associated with NAFLD, although our understanding of the biology underlying their role is still emerging. The goal of this review is to present an overview of the current state of knowledge of mi RNAs involved in the development of NAFLD across a range of in vitro and in vivo models, including mi RNAs that contribute to pathological mechanisms related to fatty liver in humans. Much less is known about the specific targets of mi RNAs in cells, nor the molecular mechanisms involved in the development and progression NAFLD and related outcomes. More recently, the identification and validation of mi RNA signatures in serum may facilitate the development of improved methods for diagnosis and clinical monitoring of disease progression.展开更多
Type 2 diabetes(T2D) and cardiovascular disease(CVD) share many risk factors such as obesity,unhealthy lifestyle,and metabolic syndrome,whose accumulation over years leads to disease onset.However,while lowering plasm...Type 2 diabetes(T2D) and cardiovascular disease(CVD) share many risk factors such as obesity,unhealthy lifestyle,and metabolic syndrome,whose accumulation over years leads to disease onset.However,while lowering plasma low-density lipoprotein cholesterol(LDLC) is cardio-protective,novel evidence have recognised a role for common LDLC-lowering variants(e.g.in HMGCR,PCSK9,and LDLR) and widely used hypocholesterolemic drugs that mimic the effects of some of these variants(statins) in higher risk for T2D.As these conditions decrease plasma LDLC by increasing tissue-uptake of LDL,a role for LDL receptor(LDLR)pathway was proposed.While underlying mechanisms remain to be fully elucidated,work from our lab reported that native LDL directly provoke the dysfunction of human white adipose tissue(WAT) and the activation of WAT NLRP3(Nucleotide-binding domain and Leucine-rich repeat Receptor,containing a Pyrin domain 3)inflammasome,which play a major role in the etiology of T2D.However,while elevated plasma numbers of apolipoprotein B(apoB)-containing lipoproteins(measured as apoB,mostly as LDL) is associated with WAT dysfunction and related risk factors for T2D in our cohort,this relation was strengthened in regression analysis by lower plasma proprotein convertase subtilisin/kexin type 9(PCSK9).This supports a central role for upregulated pathway of LDLR and/or other receptors regulated by PCSK9 such as cluster of differentiation 36(CD36) in LDL-induced anomalies.Targeting receptor-mediated uptake of LDL into WAT may reduce WAT inflammation,WAT dysfunction,and related risk for T2D without increasing the risk for CVD.展开更多
基金Supported by The National Institutes of Health DK091601(JKD and GSG),P30 DK072488(GSG and CDS)the Translational Genomics Research Institute
文摘Nonalcoholic fatty liver disease or nonalcoholic fatty liver disease(NAFLD) refers to a group of disorders that arise from the accrual of fat in hepatocytes. Although various factors have been associated with the development of NAFLD, including genetic predisposition and environmental exposures, little is known aboutthe underlying pathogenesis of the disease. Research efforts are ongoing to identify biological targets and signaling pathways that mediate NAFLD. Emerging evidence has implicated a role for micro RNAs(mi RNAs), short single-stranded molecules that regulate gene expression either transcriptionally, through targeting of promoter regions, or post-transcriptionally, by blocking translation or promoting cleavage of specific target m RNAs. Several mi RNAs have been associated with NAFLD, although our understanding of the biology underlying their role is still emerging. The goal of this review is to present an overview of the current state of knowledge of mi RNAs involved in the development of NAFLD across a range of in vitro and in vivo models, including mi RNAs that contribute to pathological mechanisms related to fatty liver in humans. Much less is known about the specific targets of mi RNAs in cells, nor the molecular mechanisms involved in the development and progression NAFLD and related outcomes. More recently, the identification and validation of mi RNA signatures in serum may facilitate the development of improved methods for diagnosis and clinical monitoring of disease progression.
基金funded by Canadian Institutes of Health Research。
文摘Type 2 diabetes(T2D) and cardiovascular disease(CVD) share many risk factors such as obesity,unhealthy lifestyle,and metabolic syndrome,whose accumulation over years leads to disease onset.However,while lowering plasma low-density lipoprotein cholesterol(LDLC) is cardio-protective,novel evidence have recognised a role for common LDLC-lowering variants(e.g.in HMGCR,PCSK9,and LDLR) and widely used hypocholesterolemic drugs that mimic the effects of some of these variants(statins) in higher risk for T2D.As these conditions decrease plasma LDLC by increasing tissue-uptake of LDL,a role for LDL receptor(LDLR)pathway was proposed.While underlying mechanisms remain to be fully elucidated,work from our lab reported that native LDL directly provoke the dysfunction of human white adipose tissue(WAT) and the activation of WAT NLRP3(Nucleotide-binding domain and Leucine-rich repeat Receptor,containing a Pyrin domain 3)inflammasome,which play a major role in the etiology of T2D.However,while elevated plasma numbers of apolipoprotein B(apoB)-containing lipoproteins(measured as apoB,mostly as LDL) is associated with WAT dysfunction and related risk factors for T2D in our cohort,this relation was strengthened in regression analysis by lower plasma proprotein convertase subtilisin/kexin type 9(PCSK9).This supports a central role for upregulated pathway of LDLR and/or other receptors regulated by PCSK9 such as cluster of differentiation 36(CD36) in LDL-induced anomalies.Targeting receptor-mediated uptake of LDL into WAT may reduce WAT inflammation,WAT dysfunction,and related risk for T2D without increasing the risk for CVD.
