Lipolysis, and not hepatic lipogenesis, is the primary modulator of triglyceride levels in streptozotocin-induced diabetic mice

Arterioscler Thromb Vasc Biol. 2015 Jan;35(1):102-10. doi: 10.1161/ATVBAHA.114.304615. Epub 2014 Nov 13.

Abstract

Objective: Diabetic hypertriglyceridemia is thought to be primarily driven by increased hepatic de novo lipogenesis. However, experiments in animal models indicated that insulin deficiency should decrease hepatic de novo lipogenesis and reduce plasma triglyceride levels.

Approach and results: To address the discrepancy between human data and genetically altered mouse models, we investigated whether insulin-deficient diabetic mice had triglyceride changes that resemble those in diabetic humans. Streptozotocin-induced insulin deficiency increased plasma triglyceride levels in mice. Contrary to the mouse models with impaired hepatic insulin receptor signaling, insulin deficiency did not reduce hepatic triglyceride secretion and de novo lipogenesis-related gene expression. Diabetic mice had a marked decrease in postprandial triglycerides clearance, which was associated with decreased lipoprotein lipase and peroxisome proliferator-activated receptor α mRNA levels in peripheral tissues and decreased lipoprotein lipase activity in skeletal muscle, heart, and brown adipose tissue. Diabetic heterozygous lipoprotein lipase knockout mice had markedly elevated fasting plasma triglyceride levels and prolonged postprandial triglycerides clearance.

Conclusions: Insulin deficiency causes hypertriglyceridemia by decreasing peripheral lipolysis and not by an increase in hepatic triglycerides production and secretion.

Keywords: diabetes mellitus; hypertriglyceridemia; lipoprotein lipase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Animals
  • Biomarkers / blood
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism*
  • Hypertriglyceridemia / blood
  • Hypertriglyceridemia / chemically induced
  • Hypertriglyceridemia / genetics
  • Hypertriglyceridemia / metabolism*
  • Insulin / blood*
  • Lipogenesis
  • Lipolysis*
  • Lipoprotein Lipase / deficiency
  • Lipoprotein Lipase / genetics
  • Lipoprotein Lipase / metabolism
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • Myocardium / metabolism
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • PPAR delta / genetics
  • PPAR delta / metabolism
  • Postprandial Period
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Streptozocin*
  • Time Factors
  • Triglycerides / blood*

Substances

  • Biomarkers
  • Blood Glucose
  • Insulin
  • PPAR alpha
  • PPAR delta
  • RNA, Messenger
  • Triglycerides
  • Streptozocin
  • Lipoprotein Lipase