Free fatty acids sensitize hepatocytes to bile acid-induced apoptosis.
Delivery of free fatty acids to the liver in nonalcoholic fatty liver disease (NAFLD) may render hepatocytes more vulnerable to glycochenodeoxycholic acid (GCDCA)-induced apoptosis. Fat overloading was induced in HepG2-Ntcp cells and primary rat hepatocytes by incubation with palmitic or oleic acid. Apoptosis was quantified by measuring caspase 3/7 activity and transcription of interleukin (IL) 8 and IL-22 by quantitative real-time PCR. Oleic acid (500 microM) alone did not induce apoptosis, while palmitic acid (500 microM) increased apoptosis 5-fold. GCDCA did not induce significant apoptosis at low micromolar concentrations (5-30 microM) in non-steatotic cells. However, at the same concentrations, GCDCA increased apoptosis 3-fold in oleic acid-pretreated HepG2-Ntcp cells and 3.5-fold in primary rat hepatocytes. Pretreatment with oleic acid increased GCDCA-induced gene transcription of the proinflammatory cytokines IL-8 and IL-22 5-fold and 19-fold, respectively. Thus, low levels of cholestasis normally not considered harmful could advance liver injury in patients with NAFLD.
Pusl
Thomas
T
Department of Medicine II-Grosshadern, University of Munich, Marchioninistrasse 15, 81377 Munich, Germany.
Wild
Nadine
N
Vennegeerts
Timo
T
Wimmer
Ralf
R
Göke
Burkhard
B
Brand
Stephan
S
Rust
Christian
C
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005223:Fats / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism* / Q000494:pharmacology; D005999:Glycochenodeoxycholic Acid / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D019301:Oleic Acid / Q000378:metabolism / Q000494:pharmacology; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D005223:Fats; D005230:Fatty Acids, Nonesterified; D017382:Reactive Oxygen Species; D019301:Oleic Acid; D019308:Palmitic Acid; D005999:Glycochenodeoxycholic Acid