Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism

• Published in: Nature communications Vol. 10; no. 1; pp. 947 - 16
• Main Authors: Sasako, Takayoshi, Ohsugi, Mitsuru, Kubota, Naoto, Itoh, Shinsuke, Okazaki, Yukiko, Terai, Ai, Kubota, Tetsuya, Yamashita, Satoshi, Nakatsukasa, Kunio, Kamura, Takumi, Iwayama, Kaito, Tokuyama, Kumpei, Kiyonari, Hiroshi, Furuta, Yasuhide, Shibahara, Junji, Fukayama, Masashi, Enooku, Kenichiro, Okushin, Kazuya, Tsutsumi, Takeya, Tateishi, Ryosuke, Tobe, Kazuyuki, Asahara, Hiroshi, Koike, Kazuhiko, Kadowaki, Takashi, Ueki, Kohjiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.02.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/44; 13/89; 14; 38; 38/70; 38/88; 42; 42/41; 631/337; 64/60; 692/163; 692/4020; 692/699; 82/29; 82/58; 96/95; Animals; Biomarkers; Diabetes; Diabetes mellitus; Diabetes Mellitus - genetics; Diabetes Mellitus - metabolism; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Eating; Endoplasmic Reticulum Stress; Fatty liver; Feeding; Gene Knockdown Techniques; Glucose; Glucose Intolerance; Glucose tolerance; Homeostasis; Humanities and Social Sciences; Humans; Insulin; Insulin Resistance; Intolerance; Lipid Metabolism; Lipids; Liver; Liver - metabolism; Male; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolic disorders; Metabolism; Mice; Mice, Inbred C57BL; Mice, Obese; Middle Aged; multidisciplinary; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Obesity; Obesity - genetics; Obesity - metabolism; Protein transport; Proteins; Restoration; Science; Science (multidisciplinary); Therapeutic applications
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08591-6

Dynamic metabolic changes occur in the liver during the transition between fasting and feeding. Here we show that transient ER stress responses in the liver following feeding terminated by Sdf2l1 are essential for normal glucose and lipid homeostasis. Sdf2l1 regulates ERAD through interaction with a trafficking protein, TMED10. Suppression of Sdf2l1 expression in the liver results in insulin resistance and increases triglyceride content with sustained ER stress. In obese and diabetic mice, Sdf2l1 is downregulated due to decreased levels of nuclear XBP-1s, whereas restoration of Sdf2l1 expression ameliorates glucose intolerance and fatty liver with decreased ER stress. In diabetic patients, insufficient induction of Sdf2l1 correlates with progression of insulin resistance and steatohepatitis. Therefore, failure to build an ER stress response in the liver may be a causal factor in obesity-related diabetes and nonalcoholic steatohepatitis, for which Sdf2l1 could serve as a therapeutic target and sensitive biomarker. Endoplasmic reticulum (ER) stress has been proposed to play a role in metabolic diseases. Here, Sasako and colleagues identify stromal cell-derived factor 2 like 1 (Sdf2l1) as a regulator of the ER stress response to feeding in the liver, and suggest that its downregulation may promote diabetes and hepatic steatosis in humans.