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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 C57BL/6J (WT) mice were fed a HFD (45% kcal fat content) or a standard chow diet (chow, 12% kcal fat content) for 22weeks. 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-B p65, p-JNK and p-p38MAPK, as well as higher hepatic and serum contents of IL-6 and TNF. In mouse primary hepatocyte cultures, IL-6 and TNF 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.
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JOURNAL OF NEUROCHEMISTRY
ISSN: 0022-3042
Year: 2016
Issue: 4
Volume: 136
Page: 791-803
4 . 0 8 3
JCR@2016
5 . 3 7 2
JCR@2020
ESI Discipline: NEUROSCIENCE & BEHAVIOR;
ESI HC Threshold:177
JCR Journal Grade:2
CAS Journal Grade:3
Cited Count:
WoS CC Cited Count: 5
SCOPUS Cited Count: 10
ESI Highly Cited Papers on the List: 0 Unfold All
WanFang Cited Count:
Chinese Cited Count:
30 Days PV: 2