Apolipoprotein CIII Overexpression-Induced Hypertriglyceridemia Increases Nonalcoholic Fatty Liver Disease in Association with Inflammation and Cell Death.
Nonalcoholic fatty liver disease (NAFLD) is the principal manifestation of liver disease in obesity and metabolic syndrome. By comparing hypertriglyceridemic transgenic mice expressing apolipoprotein (apo) CIII with control nontransgenic (NTg) littermates, we demonstrated that overexpression of apoCIII, independent of a high-fat diet (HFD), produces NAFLD-like features, including increased liver lipid content; decreased antioxidant power; increased expression of TNFα, TNFαreceptor, cleaved caspase-1, and interleukin-1β; decreased expression of adiponectin receptor-2; and increased cell death. This phenotype is aggravated and additional NAFLD features are differentially induced in apoCIII mice fed a HFD. HFD induced glucose intolerance together with increased gluconeogenesis, indicating hepatic insulin resistance. Additionally, the HFD led to marked increases in plasma TNFα(8-fold) and IL-6 (60%) in apoCIII mice. Cell death signaling (Bax/Bcl2), effector (caspase-3), and apoptosis were augmented in apoCIII mice regardless of whether a HFD or a low-fat diet was provided. Fenofibrate treatment reversed several of the effects associated with diet and apoCIII expression but did not normalize inflammatory traits even when liver lipid content was fully corrected. These results indicate that apoCIII and/or hypertriglyceridemia plays a major role in liver inflammation and cell death, which in turn increases susceptibility to and the severity of diet-induced NAFLD.
Department of Structural and Functional Biology, Biology Institute, State University of Campinas, Campinas, SP, Brazil.
Adriene A
AA
Paiva
Department of Structural and Functional Biology, Biology Institute, State University of Campinas, Campinas, SP, Brazil.
Helena F
HF
Raposo
Department of Structural and Functional Biology, Biology Institute, State University of Campinas, Campinas, SP, Brazil.
Amarylis C B A
AC
Wanschel
Department of Structural and Functional Biology, Biology Institute, State University of Campinas, Campinas, SP, Brazil.
Tarlliza R
TR
Nardelli
Department of Structural and Functional Biology, Biology Institute, State University of Campinas, Campinas, SP, Brazil.
Helena C F
0000-0003-0119-6992
HC
Oliveira
D000818:Animals; D053305:Apolipoprotein C-III / Q000096:biosynthesis* / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D059305:Diet, High-Fat; D015228:Hypertriglyceridemia / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D053305:Apolipoprotein C-III; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha