Apolipoprotein CIII Overexpression-Induced Hypertriglyceridemia Increases Nonalcoholic Fatty Liver Disease in Association with Inflammation and Cell Death

• Published in: Oxidative medicine and cellular longevity Vol. 2017; no. 2017; pp. 1 - 18
• Main Authors: Nardelli, Tarlliza R., Wanschel, Amarylis C. B. A., Raposo, Helena F., Paiva, Adriene A., Oliveira, Helena C. F.
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Publishing Corporation 01.01.2017; Hindawi; John Wiley & Sons, Inc; Hindawi Limited
• Subjects: Animals; Apolipoprotein C-III - biosynthesis; Apolipoprotein C-III - metabolism; Apolipoproteins; Apoptosis; Biology; Cardiovascular disease; Care and treatment; Cell death; Cell Death - physiology; Complications and side effects; Cytokines; Development and progression; Diabetes; Diet; Diet, High-Fat; Fatty acids; Fatty liver; Gangrene; Gene expression; Genetic aspects; Health aspects; Hyperlipidemia; Hypertriglyceridemia - metabolism; Hypotheses; Inflammation; Inflammation - metabolism; Insulin; Insulin resistance; Interleukin-6 - metabolism; Lipids; Liver diseases; Male; Mice; Mice, Transgenic; Non-alcoholic Fatty Liver Disease - metabolism; Obesity; Oxidative stress; Plasma; Proteins; R&D; Research & development; Rodents; Signal Transduction; Transgenic animals; Triglycerides; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF
• ISSN: 1942-0900; 1942-0994
• DOI: 10.1155/2017/1838679

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, TNFα receptor, 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.