Journal
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
Volume 75, Issue 2, Pages 278-285Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/gerona/glz153
Keywords
NOS; LSEC; dSTORM; Aging; Insulin
Categories
Funding
- Australian National Health and Medical Research Council [1141234, 1101913]
- Ageing and Alzheimer's Research Foundation (a Division of the Medical Foundation of the University of Sydney)
- Sydney Medical School Foundation McKnight Bequest
- University of Sydney DVCR Research Equity Fellowship
- University of Tromso Faculty of Health Sciences travel grants
- National Health and Medical Research Council of Australia [1101913, 1141234] Funding Source: NHMRC
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Age-related changes in the liver sinusoidal endothelium, particularly the reduction in fenestrations, contribute to insulin resistance in old age. Metformin impacts on the aging process and improves insulin resistance. Therefore, the effects of metformin on the liver sinusoidal endothelium were studied. Metformin increased fenestrations in liver sinusoidal endothelial cells isolated from both young and old mice. Mice administered metformin in the diet for 12 months had increased fenestrations and this was associated with lower insulin levels. The effect of metformin on fenestrations was blocked by inhibitors of AMP-activated protein kinase (AMPK), endothelial nitric oxide synthase, and myosin light chain kinase phosphorylation. Metformin led to increased transgelin expression and structural changes in the actin cytoskeleton but had no effect on lactate production. Metformin also generated fenestration-like structures in SK-Hep1 cells, a liver endothelial cell line, and this was associated with increased ATP, cGMP, and mitochondrial activity. In conclusion, metformin ameliorates age-related changes in the liver sinusoidal endothelial cell via AMPK and endothelial nitric oxide pathways, which might promote insulin sensitivity in the liver, particularly in old age.
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