title: Impaired PI3K/Akt signal pathway and hepatocellular injury in high-fat fed rats.
abstract: OBJECTIVE
  to determine whether mitochondrial dysfunction resulting from high-fat diet is related to impairment of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt, also known as PKB) pathway.
  
  
  METHODS
  rat models of nonalcoholic fatty liver were established by high-fat diet feeding. The expression of total and phosphorylated P13K and Akt proteins in hepatocytes was determined by Western blotting. Degree of fat accumulation in liver was measured by hepatic triglyceride. Mitochondrial number and size were determined using quantitative morphometric analysis under transmission electron microscope. The permeability of the outer mitochondrial membrane was assessed by determining the potential gradient across this membrane.
  
  
  RESULTS
  after Wistar rats were fed with high-fat diet for 16 wk, their hepatocytes displayed an accumulation of fat (103.1 ± 12.6 vs 421.5 ± 19.7, P < 0.01), deformed mitochondria (9.0% ± 4.3% vs 83.0% ± 10.9%, P < 0.05), and a reduction in the mitochondrial membrane potential (389.385% ± 18.612% vs 249.121% ± 13.526%, P < 0.05). In addition, the expression of the phosphorylated P13K and Akt proteins in hepatocytes was reduced, as was the expression of the anti-apoptotic protein Bcl-2, while expression of the pro-apoptotic protein caspase-3 was increased. When animals were treated with pharmacological inhibitors of P13K or Akt, instead of high-fat diet, a similar pattern of hepatocellular fat accumulation, mitochondrial impairment, and change in the levels of PI3K, Akt, Bcl-2 was observed.
  
  
  CONCLUSIONS
  high-fat diet appears to inhibit the PI3K/Akt signaling pathway, which may lead to hepatocellular injury through activation of the mitochondrial membrane pathway of apoptosis.
authors.affiliation: Department of Endocrinology, First Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China.
authors.forename: Ji-Wu
authors.initials: JW
authors.lastname: Han
authors.forename: Xiao-Rong
authors.initials: XR
authors.lastname: Zhan
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Li
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.forename: Yue-Ying
authors.initials: YY
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Bao-Xin
authors.initials: BX
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000473:pathology* / Q000502:physiology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology
chemical_list: D004041:Dietary Fats; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt