MFGE8 links absorption of dietary fatty acids with catabolism of enterocyte lipid stores through HNF4γ-dependent transcription of CES enzymes.
MFGE8 links absorption of dietary fatty acids with catabolism of enterocyte lipid stores through HNF4γ-dependent transcription of CES enzymes.
复制标题
DOI：
10.1016/j.celrep.2023.112249
复制
发表时间：
2023-03-28
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
肠细胞通过在细胞质脂滴（cLDs）中储存膳食脂肪来调节餐后脂血症的程度。我们之前的研究表明，整合素配体MFGE8将膳食脂肪的吸收与甘油三酯（TG）水解酶的激活联系起来，甘油三酯（TG）水解酶分解乳糜微粒生成的cLDs。在这里，我们确定CES1D是MFGE8-αv - β5整合素途径下游的关键水解酶，该途径调节饮食源性cLDs的分解代谢。Mfge8敲除（KO）肠细胞降低了CES1D转录物和蛋白水平，降低了转录因子HNF4γ的蛋白水平。Ces1d和Hnf4γ KO小鼠都降低了肠细胞TG水解酶活性，并伴有cLDs中TG的保留。机制上，mfge8依赖性脂肪酸摄取通过CD36稳定HNF4γ蛋白水平；然后，HNF4γ增加Ces1d的转录。我们的研究发现了一个调节网络，通过将膳食脂肪吸收与一种转录因子的蛋白质稳定联系起来，从而调节餐后脂血症的严重程度，该转录因子增加了负责分解饮食来源的cLDs的水解酶的表达。肠细胞通过储存从饮食中吸收的脂质作为细胞质脂滴（cLDs）的一部分来限制餐后脂血症的严重程度。Datta等人发现了一种稳态途径，其中整合素配体MFGE8通过核受体HNF4γ和CES1水解酶将膳食脂肪吸收与cLDs水解联系起来。
Enterocytes modulate the extent of postprandial lipemia by storing dietary fats in cytoplasmic lipid droplets (cLDs). We have previously shown that the integrin ligand MFGE8 links absorption of dietary fats with activation of triglyceride (TG) hydrolases that catabolize cLDs for chylomicron production. Here, we identify CES1D as the key hydrolase downstream of the MFGE8-αvβ5 integrin pathway that regulates catabolism of diet-derived cLDs. Mfge8 knockout (KO) enterocytes have reduced CES1D transcript and protein levels and reduced protein levels of the transcription factor HNF4γ. Both Ces1d and Hnf4γ KO mice have decreased enterocyte TG hydrolase activity coupled with retention of TG in cLDs. Mechanistically, MFGE8-dependent fatty acid uptake through CD36 stabilizes HNF4γ protein level; HNF4γ then increases Ces1d transcription. Our work identifies a regulatory network that regulates the severity of postprandial lipemia by linking dietary fat absorption with protein stabilization of a transcription factor that increases expression of hydrolases responsible for catabolizing diet-derived cLDs. Enterocytes limit the severity of postprandial lipemia by storing lipids absorbed from the diet as part of cytoplasmic lipid droplets (cLDs). Datta et al. identify a homeostatic pathway in which the integrin ligand MFGE8 links dietary fat absorption with hydrolysis of cLDs through the nuclear receptor HNF4γ and CES1 hydrolases.
登录
查看更多内容
DOI：
10.1073/pnas.2102171118
发表时间：
2021-05-04
影响因子：
11.1
作者：
Datta, Ritwik;Lizama, Carlos O.;Atabai, Kamran
通讯作者：
Atabai, Kamran
影响因子：
29.4
作者：
Grossmann, J;Artinger, M;Levine, AD
通讯作者：
Levine, AD
影响因子：
6.5
作者：
Chalhoub G;Kolleritsch S;Maresch LK;Taschler U;Pajed L;Tilp A;Eisner H;Rosina P;Kien B;Radner FPW;Schicho R;Oberer M;Schoiswohl G;Haemmerle G
通讯作者：
Haemmerle G
影响因子：
3.9
作者：
Imai, T;Imoto, M;Hashimoto, M
通讯作者：
Hashimoto, M
影响因子：
56.9
作者：
Haemmerle, G;Lass, A;Zechner, R
通讯作者：
Zechner, R