title: Early inflammation-associated factors blunt sterol regulatory element-binding proteins-1-mediated lipogenesis in high-fat diet-fed APPSWE/PSEN1dE9 mouse model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) patients have an increased incidence of Type 2 diabetes (T2D); however, the underlying mechanisms are not well understood. Since AD is considered a multifactorial disease that affects both the central nerves system and periphery and the dysregulation of hepatic lipid and glucose metabolism play critical roles in T2D, we, therefore, aim to explore the influence of AD genotype on the liver during the progress of high-fat diet (HFD)-induced T2D. Fourteen-week-old female APPSWE/PSEN1dE9 (AD) mice and age-, gender-matched wild-type controls C57BL/6J (WT) mice were fed a HFD (45% kcal fat content) or a standard chow diet (chow, 12% kcal fat content) for 22 weeks. The effects of diet and genotype were analyzed. Mouse primary hepatocytes were used to decipher the underlying mechanisms. HFD induced significantly higher body weight gain, more severe hyperglycemia, glucose intolerance and hepatic insulin resistance in AD mice than in WT mice. However, AD mice showed reduced HFD-induced hepatic steatosis, and SREBP-1-mediated lipogenic signaling was activated by HFD in WT mice but not in AD mice. In addition, 14-week-old AD mice exhibited higher expression of NF-κB p65, p-JNK and p-p38MAPK, as well as higher hepatic and serum contents of IL-6 and TNFα. In mouse primary hepatocyte cultures, IL-6 and TNFα inhibited high-glucose plus insulin-induced activation of SREBP-1-mediated lipogenic signaling and biosynthesis of non-esterified fatty acid and triglyceride. Early inflammation-associated factors most likely diminish HFD-induced hepatic lipid deposition by inhibiting SREBP-1-mediated de novo lipogenesis, thus driving substrate flux to glucose production for hyperglycemia and hepatic insulin resistance in T2D development. Alzheimer's disease (AD) is a multifactorial disease affecting both central nerves system and periphery organs. Therefore, we explored the hepatic susceptibility to high-fat diet (HFD) in AD mice. We found that AD mice were resistant to HFD-induced hepatic fat accumulation in spite of more severe obesity, hyperglycemia, glucose intolerance and hepatic insulin resistance. Mechanistically, AD mice exhibited hepatic inflammation at an early stage, which inhibited sterol regulatory element-binding proteins-1 (SREBP-1)-mediated de novo lipogenesis, and most likely drive substrate flux to glucose production for hyperglycemia and hepatic insulin resistance. Cover Image for this issue: doi: 10.1111/jnc.13306.
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Le
authors.initials: L
authors.lastname: Shi
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Yongyao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Long
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
keywords: Alzheimer's disease; hepatic steatosis; high-fat diet; inflammation; type 2 diabetes