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.