Dichloroacetate Stimulates Glycogen Accumulation in Primary Hepatocytes through an Insulin-Independent Mechanism

Journal Article · Tue Jan 01 04:00:00 EST 2002 · Toxicological Sciences

DOI:https://doi.org/10.1093/toxsci/68.2.508· OSTI ID:15001826

Lingohr, Melissa K ^[1]; Bull, Richard J ^[2]; Kato-Weinstein, Junko ^[3]; Thrall, Brian D ^[4]

---

1. Washington State University
2. SELF-EMPLOYED CONSULTANTS
3. UNIVERSITY PROGRAMS
4. BATTELLE (PACIFIC NW LAB)

Dichloroacetate (DCA), a by-product of water chlorination, causes liver cancer in B6C3F1 mice. A hallmark response observed in mice exposed to carcinogenic doses of DCA is an accumulation of hepatic glycogen content. To distinguish whether the in vivo glycogenic effect of DCA was dependent on insulin and insulin signaling proteins, experiments were conducted in isolated hepatocytes where insulin concentrations could be controlled. In hepatocytes isolated from male B6C3F1 mice, DCA increased glycogen levels in a dose-related manner, independently of insulin. The accumulation of hepatocellular glycogen induced by DCA was not the result of decreased glycogenolysis, since DCA had no effect on the rate of glucagon-stimulated glycogen breakdown. Glycogen accumulation caused by DCA treatment was not hindered by inhibitors of extracellular-regulated protein kinase kinase (Erk1/2 kinase or MEK) or p70 kDa S6 protein kinase (p70(S6K)), but was completely blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin. Similarly, insulin-stimulated glycogen deposition was not influenced by the Erk1/2 kinase inhibitor, PD098509, or the p70(S6K) inhibitor, rapamycin. Unlike DCA-stimulated glycogen deposition, PI3K-inhibition only partially blocked the glycogenic effect of insulin. DCA did not cause phosphorylation of the downstream PI3K target protein, protein kinase B (PKB/Akt). The phosphorylation of PKB/Akt did not correlate to insulin-stimulated glycogenesis either. Similar to insulin, DCA in the medium decreased IR expression in isolated hepatocytes. The results indicate DCA increases hepatocellular glycogen accumulation through a PI3K-dependent mechanism that does not involve PKB/Akt and is, at least in part, different from the classical insulin-stimulated glycogenesis pathway. Somewhat surprisingly, insulin-stimulated glycogenesis also appears not to involve PKB/Akt in isolated murine hepatocytes.

• Research Organization: Pacific Northwest National Lab., Richland, WA (US)
• Sponsoring Organization: US Department of Energy (US)
• DOE Contract Number: AC06-76RL01830
• OSTI ID: 15001826
• Report Number(s): PNWD-SA-5785
• Journal Information: Toxicological Sciences, Journal Name: Toxicological Sciences Vol. 68
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
BREAKDOWN
BY-PRODUCTS
CHLORINATION
DEPOSITION
GLYCOGEN
IN VIVO
INSULIN
LIVER
LIVER CELLS
MICE
NEOPLASMS
PHOSPHORYLATION
PHOSPHOTRANSFERASES
PROTEINS
TARGETS