OBJECTIVE Metrnl is a novel secreted protein with limited researches.In this study,we investigated metrnl tissue expression pattern in humans,and exploredthe possible role of its highest expression using animal models...OBJECTIVE Metrnl is a novel secreted protein with limited researches.In this study,we investigated metrnl tissue expression pattern in humans,and exploredthe possible role of its highest expression using animal models.METHODS We examined metrnl tissue expression pattern in a human tissue microarray containing 19types of tissues from 69 donors,and verified the highest expression in fresh human and mouse tissues.We then created an animal model of cell-specific knockout mice to study the role of metrnl.RESULTS Metrnl was the highest expressed in human gastrointestinal tract,and specifical y expressed in the intestinal epithelium.Consistently,Metrnl expression was also the highest expressed in mouse gastrointestinal tract among the detected tissues of 14 types.We developed intestinal epithelial cellspecific metrnl knockout mice with Vil in-Cre.In this animal model,metrnl levels displayed a statistically significant reduction in gut fluid,but not in blood serum.This cell specific deletion of metrnl did not affect body weight,food intake,blood glucose,colon length and histology,intestinal permeability,mucus production and mucin 2 expression under physiological conditions,but markedly reduced the expression of antimicrobial peptides,such as regenerating islet-derived 3 gamma and lactotransferrin.CONCLUSION Metrnl is rich in intestinal epithelial cells of humans and mice,mainly contributing to local gut metrnl level,and less affecting systemic circulating metrnl level.Metrnl plays a role in maintaining gut antimicrobial peptides.展开更多
OBJECTIVE Aging is an important risk factor of nonalcoholic fatty liver disease(NAFLD).Here,we investigated whether the deficiency of nicotinamide adenine dinucleotide(NAD+),a ubiquitous coenzyme,links aging with NAFL...OBJECTIVE Aging is an important risk factor of nonalcoholic fatty liver disease(NAFLD).Here,we investigated whether the deficiency of nicotinamide adenine dinucleotide(NAD+),a ubiquitous coenzyme,links aging with NAFLD.METHODS Hepatic NAD+concentration,together with the protein levels of nicotinamide phosphoribosyltransferase(NAMPT)and several other critical enzymes regulating NAD+biosynthesis,were compared between middle-aged and aged mice or patients.The influences of NAD+decline on the steatosis and steatohepatitis was evaluated in wild-type(WT)and H247A dominant-negative enzymatic-dead NAMPT transgenic mice(DN-NAMPT)under normal and high-fat diet(HFD).RESULTS Hepatic NAD+level decreased in aged mice and people.NAMPT-controlled NAD+salvage,but not de novo biosynthesis pathway,was compromised in liver of elderly mice and human.Under normal chow,middle-age DN-NAMPT mice displayed systemic NAD+reduction,and had moderate NAFLD phenotypes,including lipid accumulation,enhanced oxidative stress,triggered inflammation and impaired insulin sensitivity in liver.Allthese NAFLD phenotypes,especial y the pro-inflammatory factors release,Kupffer cell accumulation,monocytes infiltration,NLRP3 inflammasome pathway,and hepatic fibrosis(Masson’s staining and a-SMA staining),were further deteriorated under HFD challenge.Orally administration of nicotinamide riboside,a natural NAD+precursor,completely corrected these NAFLD phenotypes induced by NAD+deficiency alone or HFD,whereas adenovirusmediated SIRT1 overexpression only partially rescued these phenotypes.CONCLUSION These results provide the first evidence that aging-associated NAD+deficiency is a critical risk factor for NAFLD,and suggest that supplement of NAD+substrates may be a promising therapeutic strategy to prevent and treat NAFLD.展开更多
基金The project supported by National Natural Science Foundation of China(81130061,81202572,81373414)
文摘OBJECTIVE Metrnl is a novel secreted protein with limited researches.In this study,we investigated metrnl tissue expression pattern in humans,and exploredthe possible role of its highest expression using animal models.METHODS We examined metrnl tissue expression pattern in a human tissue microarray containing 19types of tissues from 69 donors,and verified the highest expression in fresh human and mouse tissues.We then created an animal model of cell-specific knockout mice to study the role of metrnl.RESULTS Metrnl was the highest expressed in human gastrointestinal tract,and specifical y expressed in the intestinal epithelium.Consistently,Metrnl expression was also the highest expressed in mouse gastrointestinal tract among the detected tissues of 14 types.We developed intestinal epithelial cellspecific metrnl knockout mice with Vil in-Cre.In this animal model,metrnl levels displayed a statistically significant reduction in gut fluid,but not in blood serum.This cell specific deletion of metrnl did not affect body weight,food intake,blood glucose,colon length and histology,intestinal permeability,mucus production and mucin 2 expression under physiological conditions,but markedly reduced the expression of antimicrobial peptides,such as regenerating islet-derived 3 gamma and lactotransferrin.CONCLUSION Metrnl is rich in intestinal epithelial cells of humans and mice,mainly contributing to local gut metrnl level,and less affecting systemic circulating metrnl level.Metrnl plays a role in maintaining gut antimicrobial peptides.
基金The project supported by National Natural Science Foundation of China(81373414,81130061,81473208,81422049)National 863 Plan Young Scientist Program of China(2015AA020943)Shanghai Qimingxing Project(14QA1404700)
文摘OBJECTIVE Aging is an important risk factor of nonalcoholic fatty liver disease(NAFLD).Here,we investigated whether the deficiency of nicotinamide adenine dinucleotide(NAD+),a ubiquitous coenzyme,links aging with NAFLD.METHODS Hepatic NAD+concentration,together with the protein levels of nicotinamide phosphoribosyltransferase(NAMPT)and several other critical enzymes regulating NAD+biosynthesis,were compared between middle-aged and aged mice or patients.The influences of NAD+decline on the steatosis and steatohepatitis was evaluated in wild-type(WT)and H247A dominant-negative enzymatic-dead NAMPT transgenic mice(DN-NAMPT)under normal and high-fat diet(HFD).RESULTS Hepatic NAD+level decreased in aged mice and people.NAMPT-controlled NAD+salvage,but not de novo biosynthesis pathway,was compromised in liver of elderly mice and human.Under normal chow,middle-age DN-NAMPT mice displayed systemic NAD+reduction,and had moderate NAFLD phenotypes,including lipid accumulation,enhanced oxidative stress,triggered inflammation and impaired insulin sensitivity in liver.Allthese NAFLD phenotypes,especial y the pro-inflammatory factors release,Kupffer cell accumulation,monocytes infiltration,NLRP3 inflammasome pathway,and hepatic fibrosis(Masson’s staining and a-SMA staining),were further deteriorated under HFD challenge.Orally administration of nicotinamide riboside,a natural NAD+precursor,completely corrected these NAFLD phenotypes induced by NAD+deficiency alone or HFD,whereas adenovirusmediated SIRT1 overexpression only partially rescued these phenotypes.CONCLUSION These results provide the first evidence that aging-associated NAD+deficiency is a critical risk factor for NAFLD,and suggest that supplement of NAD+substrates may be a promising therapeutic strategy to prevent and treat NAFLD.
