TTC39B destabilizes retinoblastoma protein promoting hepatic lipogenesis in a sex-specific fashion.
TTC39B destabilizes retinoblastoma protein promoting hepatic lipogenesis in a sex-specific fashion.
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DOI：
10.1016/j.jhep.2021.09.021
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发表时间：
2022-03
影响因子：
25.7
通讯作者：
Tall AR
中科院分区：
文献类型：
--
作者：
Hsieh J;Molusky MM;McCabe KM;Fotakis P;Xiao T;Tascau L;Zeana-Schliep L;DaSilva-Jardine P;Tall AR
目前，对于男性和女性对非酒精性脂肪性肝病（NAFLD）易感性存在差异的分子机制，人们了解甚少。TTC39B基因座编码一种支架蛋白，与妇科疾病相关，其缺失可使小鼠免受饮食诱导的脂肪性肝炎。本研究旨在阐明TTC39B（T39）与脂肪生成基因表达相关的分子机制，并探究其性别特异性效应。
通过在HEK293A细胞中共表达，验证了蛋白质 - 蛋白质相互作用算法预测的新型T39/pRb相互作用。在具有pRb或其下游效应因子E2F1遗传缺陷的饮食诱导NAFLD小鼠以及原代人肝细胞中，使用反义寡核苷酸（ASO）敲低T39。
T39通过其C端TPR结构域与pRb相互作用，并促进pRb的蛋白酶体降解。在雌性小鼠中，T39缺失以pRb和E2F1依赖的方式降低脂肪生成基因的mRNA水平，尤其是Pnpla3。相比之下，在雄性小鼠中，T39缺失导致脂肪生成基因表达的降低幅度小得多，且不依赖于pRb/E2F1。T39还通过N端FFAT基序与VAPB相互作用，并稳定VAPB与SCAP的相互作用。卵巢切除术可消除T39敲低对肝脏pRb/E2F1/Pnpla3轴的影响。在两性中，T39敲低均可独立于pRb降低SCAP水平。在原代人肝细胞中，T39敲低可降低女性而非男性中PNPLA3及其他脂肪生成基因的表达。
我们发现了肝脏脂肪生成基因调控中存在的一种保守的性别二态性，T39的作用在雌性中通过pRb/E2F1介导，在两性中均通过VAPB/SCAP介导。抑制T39可能是下调PNPLA3并治疗女性NAFLD的一种新策略。
在雌性个体中，TTC39B降解肝脏中的一种肿瘤抑制因子，以促进新脂肪的合成以及非酒精性脂肪性肝病主要遗传风险因子的表达。TTC39B是治疗非酒精性脂肪性肝病，尤其是女性患者的潜在治疗靶点。
Molecular mechanisms underlying the different susceptibility of men and women to NAFLD are poorly understood. The TTC39B locus encodes a scaffolding protein, associates with gynecological disorders and its deletion protects mice from diet-induced steatohepatitis. This study aimed to elucidate the molecular mechanisms linking TTC39B (T39) to the expression of lipogenic genes and to explore sex-specific effects. Co-expression in HEK293A cells validated the novel T39/pRb interaction predicted by a protein-protein interaction algorithm. T39 was knocked down using antisense oligonucleotide (ASO) in dietary NAFLD mice with genetic deficiency of pRb or its downstream effector E2F1 and in primary human hepatocytes. T39 interacts with pRb via its C-terminal TPR domain and promotes its proteasomal degradation. In female mice T39 deficiency reduces the mRNA of lipogenic genes, especially Pnpla3, in a pRb- and E2F1-dependent manner. In contrast, in male mice, T39 deficiency results in a much smaller reduction in lipogenic gene expression that is independent of pRb/E2F1. T39 also interacts with VAPB via an N-terminal FFAT motif and stabilizes the interaction of VAPB with SCAP. Ovariectomy abolishes the effect of T39 knockdown on the hepatic pRb/E2F1/Pnpla3 axis. In both sexes T39 knockdown reduces SCAP independent of pRb. In human primary hepatocytes, T39 knockdown reduces expression of PNPLA3 and other lipogenic genes in women but not men. We have uncovered a conserved sexual dimorphism in the regulation of hepatic lipogenic genes with effects of T39 mediated through pRb/E2F1 in females and VAPB/SCAP in both sexes. T39 inhibition could be a novel strategy to downregulate PNPLA3 and treat NAFLD in women. In females, TTC39B degrades a tumor suppressor in the liver to promote the synthesis of new fat and expression of a major genetic risk factor for nonalcoholic fatty liver disease. TTC39B is a potential therapeutic target for nonalcoholic fatty liver disease, especially in women.
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影响因子：
8
作者：
Luukkonen, Panu K.;Nick, Auli;Yki-Javinen, Hannele
通讯作者：
Yki-Javinen, Hannele
DOI：
10.1002/hep.24517
发表时间：
2011-09-02
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Miller AM;Wang H;Bertola A;Park O;Horiguchi N;Ki SH;Yin S;Lafdil F;Gao B
通讯作者：
Gao B
全基因组关联荟萃分析产生了20个与胆结石疾病相关的基因座。
影响因子：
16.6
作者：
Ferkingstad E;Oddsson A;Gretarsdottir S;Benonisdottir S;Thorleifsson G;Deaton AM;Jonsson S;Stefansson OA;Norddahl GL;Zink F;Arnadottir GA;Gunnarsson B;Halldorsson GH;Helgadottir A;Jensson BO;Kristjansson RP;Sveinbjornsson G;Sverrisson DA;Masson G;Olafsson I;Eyjolfsson GI;Sigurdardottir O;Holm H;Jonsdottir I;Olafsson S;Steingrimsdottir T;Rafnar T;Bjornsson ES;Thorsteinsdottir U;Gudbjartsson DF;Sulem P;Stefansson K
通讯作者：
Stefansson K
影响因子：
29.4
作者：
Lambert JE;Ramos-Roman MA;Browning JD;Parks EJ
通讯作者：
Parks EJ
影响因子：
8.1
作者：
McCabe, Kristin M.;Hsieh, Joanne;Tall, Alan R.
通讯作者：
Tall, Alan R.