Deletion of Macrophage Mineralocorticoid Receptor Protects Hepatic Steatosis and Insulin Resistance Through ERα/HGF/Met Pathway.
Although the importance of macrophages in nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) has been recognized, how macrophages affect hepatocytes remains elusive. Mineralocorticoid receptor (MR) has been implicated to play important roles in NAFLD and T2DM. However, cellular and molecular mechanisms are largely unknown. We report that myeloid MR knockout (MRKO) improves glucose intolerance, insulin resistance, and hepatic steatosis in obese mice. Estrogen signaling is sufficient and necessary for such improvements. Hepatic gene and protein expression suggests that MRKO reduces hepatic lipogenesis and lipid storage. In the presence of estrogen, MRKO in macrophages decreases lipid accumulation and increases insulin sensitivity of hepatocytes through hepatocyte growth factor (HGF)/Met signaling. MR directly regulates estrogen receptor 1 (Esr1[encoding ERα]) in macrophages. Knockdown of hepatic Met eliminates the beneficial effects of MRKO in female obese mice. These findings identify a novel MR/ERα/HGF/Met pathway that conveys metabolic signaling from macrophages to hepatocytes in hepatic steatosis and insulin resistance and provide potential new therapeutic strategies for NAFLD and T2DM.
Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
Yu-Yao
YY
Zhang
Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
Chao
C
Li
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
Gao-Feng
GF
Yao
Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
Lin-Juan
LJ
Du
Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
Yuan
Y
Liu
Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
Xiao-Jun
XJ
Zheng
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
Shuai
S
Yan
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
Jian-Yong
JY
Sun
Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yan
Y
Liu
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
Ming-Zhu
MZ
Liu
Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Xiaoran
X
Zhang
Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Gang
G
Wei
Department of Infectious Diseases, Ren-Min Hospital of Wuhan University, Wuhan, China.
Wenxin
W
Tong
Department of Infectious Diseases, Ren-Min Hospital of Wuhan University, Wuhan, China.
Xiaobei
X
Chen
Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA.|David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA.
Yong
Y
Wu
Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shuyang
S
Sun
Shanghai Cancer Center and Institutes of Biomedical Sciences, Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, Fudan University, Shanghai, China.
Suling
S
Liu
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
Qiurong
Q
Ding
Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Ying
Y
Yu
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
Huiyong
H
Yin
Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China duansz@shsmu.edu.cn.|Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Sheng-Zhong
SZ
Duan
D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D005951:Glucose Tolerance Test; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D050155:Lipogenesis; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese / Q000235:genetics* / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D000067996:RAW 264.7 Cells; D018161:Receptors, Mineralocorticoid / Q000235:genetics*; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism
D047628:Estrogen Receptor alpha; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D018161:Receptors, Mineralocorticoid; D014280:Triglycerides; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met