Defective Lipid Droplet-Lysosome Interaction Causes Fatty Liver Disease as Evidenced by Human Mutations in TMEM199 and CCDC115.
Defective Lipid Droplet-Lysosome Interaction Causes Fatty Liver Disease as Evidenced by Human Mutations in TMEM199 and CCDC115.
复制标题
人类 TMEM199 和 CCDC115 突变证明，有缺陷的脂滴-溶酶体相互作用会导致脂肪肝。
DOI：
10.1016/j.jcmgh.2021.09.013
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发表时间：
2022
影响因子：
7.2
通讯作者：
Holleboom AG
中科院分区：
文献类型：
--
作者：
Larsen LE;van den Boogert MAW;Rios-Ocampo WA;Jansen JC;Conlon D;Chong PLE;Levels JHM;Eilers RE;Sachdev VV;Zelcer N;Raabe T;He M;Hand NJ;Drenth JPH;Rader DJ;Stroes ESG;Lefeber DJ;Jonker JW;Holleboom AG
Recently, novel inborn errors of metabolism were identified because of mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia, and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell models, and a mouse model. Patients with TMEM199 and CCDC115 mutations displayed hyperlipidemia, characterized by increased levels of lipoproteins in the very low density lipoprotein range. HepG2 hepatoma cells, in which the expression of TMEM199 and CCDC115 was silenced, and induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells from patients with TMEM199 mutations showed markedly increased secretion of apolipoprotein B (apoB) compared with controls. A mouse model for TMEM199 deficiency with a CRISPR/Cas9-mediated knock-in of the human A7E mutation had marked hepatic steatosis on chow diet. Plasma N-glycans were hypogalactosylated, consistent with the patient phenotype, but no clear plasma lipid abnormalities were observed in the mouse model. In the siTMEM199 and siCCDC115 HepG2 hepatocyte models, increased numbers and size of lipid droplets were observed, including abnormally large lipid droplets, which colocalized with lysosomes. Excessive de novo lipogenesis, failing oxidative capacity, and elevated lipid uptake were not observed. Further investigation of lysosomal function revealed impaired acidification combined with impaired autophagic capacity. Our data suggest that the hypercholesterolemia in TMEM199 and CCDC115 deficiency is due to increased secretion of apoB-containing particles. This may in turn be secondary to the hepatic steatosis observed in these patients as well as in the mouse model. Mechanistically, we observed impaired lysosomal function characterized by reduced acidification, autophagy, and increased lysosomal lipid accumulation. These findings could explain the hepatic steatosis seen in patients and highlight the importance of lipophagy in fatty liver disease. Because this pathway remains understudied and its regulation is largely untargeted, further exploration of this pathway may offer novel strategies for therapeutic interventions to reduce lipotoxicity in fatty liver disease.
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影响因子：
29
作者：
Holleboom AG;Karlsson H;Lin RS;Beres TM;Sierts JA;Herman DS;Stroes ES;Aerts JM;Kastelein JJ;Motazacker MM;Dallinga-Thie GM;Levels JH;Zwinderman AH;Seidman JG;Seidman CE;Ljunggren S;Lefeber DJ;Morava E;Wevers RA;Fritz TA;Tabak LA;Lindahl M;Hovingh GK;Kuivenhoven JA
通讯作者：
Kuivenhoven JA
细胞显微镜和基于荧光的细胞内细胞器中的腔pH测量。
影响因子：
5.5
作者：
Ma L;Ouyang Q;Werthmann GC;Thompson HM;Morrow EM
通讯作者：
Morrow EM
MTORC1通过需要液泡H（+）ATPase的内而外机制感测。
DOI：
10.1126/science.1207056
发表时间：
2011-11-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Zoncu R;Bar-Peled L;Efeyan A;Wang S;Sancak Y;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
64.8
作者：
Singh, Rajat;Kaushik, Susmita;Wang, Yongjun;Xiang, Youqing;Novak, Inna;Komatsu, Masaaki;Tanaka, Keiji;Cuervo, Ana Maria;Czaja, Mark J.
通讯作者：
Czaja, Mark J.
影响因子：
13.5
作者：
Cayo, Max A.;Cai, Jun;DeLaForest, Ann;Noto, Fallon K.;Nagaoka, Masato;Clark, Brian S.;Collery, Ross F.;Si-Tayeb, Karim;Duncan, Stephen A.
通讯作者：
Duncan, Stephen A.