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- Title
Early inflammation-associated factors blunt sterol regulatory element-binding proteins-1-mediated lipogenesis in high-fat diet-fed APP<sub> SWE</sub> /PSEN1dE9 mouse model of Alzheimer's disease.
- Authors
Tang, Ying; Peng, Yunhua; Liu, Jing; Shi, Le; Wang, Yongyao; Long, Jiangang; Liu, Jiankang
- 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 APP SWE / PSEN1dE9 ( AD) mice and age-, gender-matched wild-type controls C57 BL/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-p38 MAPK, 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.
- Subjects
ANIMAL models of Alzheimer's disease; STEROL regulatory element-binding proteins; ALZHEIMER'S disease treatment; LIPID synthesis; HIGH-fat diet; CELLULAR signal transduction; MAMMALS
- Publication
Journal of Neurochemistry, 2016, Vol 136, Issue 4, p791
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/jnc.13437