Li-Hua Zhu1, Aibing Wang2, Pengcheng Luo3, Xinan Wang1, Ding-Sheng Jiang1, Wei Deng1, Xiaofei Zhang4, Tao Wang1, Yi Liu4, Lu Gao5, Shumin Zhang1, Xiaodong Zhang4, Jie Zhang3, Hongliang Li6. 1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China. 2. College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China. 3. Department of Urology, Renmin Hospital of Wuhan University, 99, Ziyang Rd, Wuhan, Hubei Province 430060, China; Huangshi Central Hospital, Hubei Polytechnic University, Huangshi, Hubei Province 435000, China. 4. College of Life Sciences, Wuhan University, Wuhan 430072, China. 5. Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. 6. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China. Electronic address: lihl@whu.edu.cn.
Abstract
BACKGROUND & AIMS: Obesity and its related pathologies, such as hepatic steatosis, are associated with chronic inflammation and insulin resistance (IR), which contribute to cardiovascular disease. Our previous studies indicated that Spondin 2 has a protective role in the context of cardiovascular and cerebrovascular diseases. Whether Spondin 2 is also associated with the development of hepatic steatosis and IR remains unclear. METHODS: Wild-type mice, Spondin 2-knockout (KO) mice, hepatic-specific Spondin 2 transgenic (Spondin 2-TG) mice, high fat diet (HFD)-induced obese mice injected with an adenovirus expressing Spondin 2-specific shRNA or a Spondin 2 mutant and genetically obese (ob/ob) mice injected with an adenovirus expressing Spondin 2 were fed normal chow (NC) or HFD for indicated time to induce obesity, hepatic steatosis, inflammation, and IR. Biomedical, histological, and metabolic analyses were conducted to identify pathologic alterations in these mice. The molecular mechanisms of Spondin 2 functions were explored in mice and in hepatocytes or cell lines. RESULTS: Consistent with Spondin 2 repression in the livers of HFD-induced and ob/ob mice, the Spondin 2-KO or hepatic-specific Spondin 2 knockdown mice exhibited more severe obesity, hepatic steatosis, inflammation, and IR upon HFD. Conversely, these pathological conditions were significantly improved in the Spondin 2-TG mice or Spondin 2-overexpressing ob/ob mice. Spondin 2 interacts with PPARα to regulate PPARα-target genes, thereby improving the pathological phenotypes. In contrast, the hepatic overexpression of mutant Spondin 2 without the PPARα-interacting domain failed to improve the aggravated phenotypes observed in the Spondin 2-KO mice. CONCLUSION: Spondin 2 regulates hepatic lipid metabolism and alleviates hepatic steatosis, obesity, inflammation, and IR in mice via its interaction with PPARα.
BACKGROUND & AIMS:Obesity and its related pathologies, such as hepatic steatosis, are associated with chronic inflammation and insulin resistance (IR), which contribute to cardiovascular disease. Our previous studies indicated that Spondin 2 has a protective role in the context of cardiovascular and cerebrovascular diseases. Whether Spondin 2 is also associated with the development of hepatic steatosis and IR remains unclear. METHODS: Wild-type mice, Spondin 2-knockout (KO) mice, hepatic-specific Spondin 2 transgenic (Spondin 2-TG) mice, high fat diet (HFD)-induced obesemice injected with an adenovirus expressing Spondin 2-specific shRNA or a Spondin 2 mutant and genetically obese (ob/ob) mice injected with an adenovirus expressing Spondin 2 were fed normal chow (NC) or HFD for indicated time to induce obesity, hepatic steatosis, inflammation, and IR. Biomedical, histological, and metabolic analyses were conducted to identify pathologic alterations in these mice. The molecular mechanisms of Spondin 2 functions were explored in mice and in hepatocytes or cell lines. RESULTS: Consistent with Spondin 2 repression in the livers of HFD-induced and ob/ob mice, the Spondin 2-KO or hepatic-specific Spondin 2 knockdown mice exhibited more severe obesity, hepatic steatosis, inflammation, and IR upon HFD. Conversely, these pathological conditions were significantly improved in the Spondin 2-TG mice or Spondin 2-overexpressing ob/ob mice. Spondin 2 interacts with PPARα to regulate PPARα-target genes, thereby improving the pathological phenotypes. In contrast, the hepatic overexpression of mutant Spondin 2 without the PPARα-interacting domain failed to improve the aggravated phenotypes observed in the Spondin 2-KO mice. CONCLUSION:Spondin 2 regulates hepatic lipid metabolism and alleviates hepatic steatosis, obesity, inflammation, and IR in mice via its interaction with PPARα.