Aluminum-induced mitochondrial dysfunction leads to lipid accumulation in human hepatocytes: a link to obesity.
Mitochondrial dysfunction is the cause of a variety of pathologies associated with high energy-requiring tissues like the brain and muscles. Here we show that aluminum (Al) perturbs oxidative-ATP production in human hepatocytes (HepG2 cells). This Al-induced mitochondrial dysfunction promotes enhanced lipogenesis and the accumulation of the very low density lipoprotein (VLDL). Al-stressed HepG2 cells secreted more cholesterol, lipids and proteins than control cells. The level of apolipoprotein B-100 (ApoB-100) was markedly increased in the culture medium of the cells exposed to Al. (13)C-NMR and HPLC studies revealed a metabolic profile favouring lipid production and lowered ATP synthesis in Al-treated cells. Electrophoretic and immunoblot analyses pointed to increased activities and expression of lipogenic enzymes such as glycerol 3-phosphate dehydrogenase (G3PDH), acetyl CoA carboxylase (ACC) and ATP-citrate lyase (CL) in the hepatocytes exposed to Al, and a sharp diminution of enzymes mediating oxidative phosphorylation. D-Fructose elicited the maximal secretion of VLDL in the Al-challenged cells. These results suggest that the Al-evoked metabolic shift favours the accumulation of lipids at the expense of oxidative energy production in hepatocytes.
Mailloux
Ryan
R
Department of Chemistry and Biochemistry, Laurentian University, Ontario, Canada.
Lemire
Joseph
J
Appanna
Vasu
V
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000535:Aluminum / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D050356:Lipid Metabolism; D009682:Magnetic Resonance Spectroscopy; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D010772:Phosphotungstic Acid / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology
D010772:Phosphotungstic Acid; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D000535:Aluminum; D005947:Glucose; D015032:Zinc