Endoplasmic reticulum stress induces hepatic steatosis via increased expression of the hepatic very low-density lipoprotein receptor

被引:162
作者
Jo, Hyunsun [1 ]
Choe, Sung Sik [1 ]
Shin, Kyung Cheul [1 ]
Jang, Hagoon [1 ]
Lee, Jae Ho [1 ]
Seong, Je Kyung [2 ,3 ]
Back, Sung Hoon [5 ]
Kim, Jae Bum [1 ,4 ]
机构
[1] Seoul Natl Univ, Sch Biol Sci, Inst Mol Biol & Genet, Seoul, South Korea
[2] Seoul Natl Univ, Dept Anat & Cell Biol, Coll Vet Med, Seoul, South Korea
[3] Seoul Natl Univ, Res Inst Vet Sci, Seoul, South Korea
[4] Seoul Natl Univ, Dept Biophys & Chem Biol, Seoul, South Korea
[5] Univ Ulsan, Sch Biol Sci, World Class Univ, Ulsan 680749, South Korea
关键词
UNFOLDED PROTEIN RESPONSE; VLDL RECEPTOR; ER STRESS; INSULIN-RESISTANCE; APOLIPOPROTEIN-E; GENE-EXPRESSION; KNOCKOUT MICE; METABOLISM; SECRETION; ACTIVATION;
D O I
10.1002/hep.26126
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Recent evidence suggests that obese animals exhibit increased endoplasmic reticulum (ER) stress in the liver and adipose tissue. Although ER stress is closely associated with lipid homeostasis, it is largely unknown how ER stress contributes to hepatic steatosis. In this study, we demonstrate that the induction of ER stress stimulates hepatic steatosis through increased expression of the hepatic very low-density lipoprotein receptor (VLDLR). Among the unfolded protein response sensors, the protein kinase RNA-like ER kinaseactivating transcription factor 4 signaling pathway was required for hepatic VLDLR up-regulation. In primary hepatocytes, ER stressdependent VLDLR expression induced intracellular triglyceride accumulation in the presence of very low-density lipoprotein. Moreover, ER stressdependent hepatic steatosis was diminished in the livers of VLDLR-deficient and apolipoprotein Edeficient mice compared with wild-type mice. In addition, the VLDLR-deficient mice exhibited decreased hepatic steatosis upon high-fat diet feeding. Conclusion: These data suggest that ER stressdependent expression of hepatic VLDLR leads to hepatic steatosis by increasing lipoprotein delivery to the liver, which might be a novel mechanism explaining ER stressinduced hepatic steatosis. (HEPATOLOGY 2013;57:13661377)
引用
收藏
页码:1366 / 1377
页数:12
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