LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance
Sijia He, Jiyoon Ryu, Juanhong Liu, Hairong Luo, Ying Lv, Paul R. Langlais, Jie Wen, Feng Dong, Zhe Sun, Wenjuan Xia, Jane L. Lynch, Ravindranath Duggirala, Bruce J. Nicholson, Mengwei Zang, Yuguang Shi, Fang Zhang, Feng Liu, Juli Bai, Lily Q. Dong
Sijia He, Jiyoon Ryu, Juanhong Liu, Hairong Luo, Ying Lv, Paul R. Langlais, Jie Wen, Feng Dong, Zhe Sun, Wenjuan Xia, Jane L. Lynch, Ravindranath Duggirala, Bruce J. Nicholson, Mengwei Zang, Yuguang Shi, Fang Zhang, Feng Liu, Juli Bai, Lily Q. Dong
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Research Article Endocrinology Metabolism

LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance

Abstract

Dysregulation in adipokine biosynthesis and function contributes to obesity-induced metabolic diseases. However, the identities and functions of many of the obesity-induced secretory molecules remain unknown. Here, we report the identification of leucine-rich alpha-2-glycoprotein 1 (LRG1) as an obesity-associated adipokine that exacerbates high fat diet–induced hepatosteatosis and insulin resistance. Serum levels of LRG1 were markedly elevated in obese humans and mice compared with their respective controls. LRG1 deficiency in mice greatly alleviated diet-induced hepatosteatosis, obesity, and insulin resistance. Mechanistically, LRG1 bound with high selectivity to the liver and promoted hepatosteatosis by increasing de novo lipogenesis and suppressing fatty acid β-oxidation. LRG1 also inhibited hepatic insulin signaling by downregulating insulin receptor substrates 1 and 2. Our study identified LRG1 as a key molecule that mediates the crosstalk between adipocytes and hepatocytes in diet-induced hepatosteatosis and insulin resistance. Suppressing LRG1 expression and function may be a promising strategy for the treatment of obesity-related metabolic diseases.

Authors

Sijia He, Jiyoon Ryu, Juanhong Liu, Hairong Luo, Ying Lv, Paul R. Langlais, Jie Wen, Feng Dong, Zhe Sun, Wenjuan Xia, Jane L. Lynch, Ravindranath Duggirala, Bruce J. Nicholson, Mengwei Zang, Yuguang Shi, Fang Zhang, Feng Liu, Juli Bai, Lily Q. Dong

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Figure 6

LRG1 contributes to diet-induced hepatic steatosis through suppressing β-oxidation and promoting de novo lipogenesis.

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LRG1 contributes to diet-induced hepatic steatosis through suppressing β...
Lrg1KO mice and WT control mice were under HFD feeding for 16 weeks. (A) Liver triglyceride content, (B) liver cholesterol levels, (C) serum triglyceride contents, and (D) serum cholesterol levels of these mice were detected (n = 7 mice/group). qPCR determination of the expression of genes involved in lipid uptake (E), lipid export (F), and fatty acid β-oxidation (G) in the liver tissues of Lrg1KO and WT littermates fed a HFD for 16 weeks (n = 8–10 mice/group). (H) The relative lipogenic protein levels from the liver tissues of these mice as quantified from Western blots by Image J (4 mice/group). (I) Fatty acid β-oxidation in primary hepatocytes treated with PBS or LRG1 (20 μg/mL) overnight was determined by using 14C-labeled palmitic acid as substrate (n = 3/treatment group). (J) Lipogenesis in primary hepatocytes treated with LRG1 or insulin overnight was determined by using 14C-labeled acetic acid as a substrate (n = 3/treatment group). All cell experiments were independently repeated for 3 times. Data represent mean ± SEM. Unpaired 2-tailed t test for (A–I). One-way ANOVA followed by Tukey’s test for J. *P ≤ 0.05, **P ≤ 0.01, ****P ≤ 0.0001. (K) A proposed model on the mechanism by which LRG1 mediates obesity-induced hepatic steatosis and insulin resistance. Obesity-induced LRG1 production in adipose tissue activates SREBP1 in the liver via an endocrinal mechanism, leading to enhanced de novo lipogenesis and suppressed fatty acid β-oxidation and consequent hepatic steatosis. LRG1 also inhibits insulin signaling by suppressing IRS1/2 expression, contributing to hepatic insulin resistance and hyperglycemia.