Interleukin-6 mediates hepatic hypersecretion of apolipoprotein B

Abstract

Obesity and type 2 diabetes are associated with insulin resistance (IR), increased circulating proinflammatory cytokines, and hypertriglyceridemia, the latter being caused by overproduction of hepatic very low density lipoprotein (VLDL). One cytokine strongly linked with development of hepatic IR is interleukin-6 (IL-6). Our objective was to evaluate IL-6 effects on hepatic apolipoprotein B (apoB) and VLDL secretion and to examine possible linkages between cytokine signaling and insulin-suppressive effects on lipoprotein secretion. Of the cytokines examined, only IL-6 stimulated secretion of apoB-containing lipoproteins in a dose-dependent manner. Both B100 and B48 secretion were significantly increased in VLDL and in lipoproteins with a density >1.019 g/ml. The ability of insulin to suppress hepatic apoB secretion was maintained in hepatocytes treated with IL-6. Pulse-chase studies indicated that enhanced apoB synthesis was the primary mechanism for increased lipoprotein secretion, which corresponded with higher abundance of apoB mRNA. Because IL-6 did not alter the decay rate of apoB mRNA transcripts, results support that increased apoB mRNA levels are the result of enhanced apob gene transcription. Increased apoB-lipoprotein secretion was also detected with oncostatin M (OSM), supporting involvement of the signal-transducing protein, gp130. Increased suppressor of cytokine signaling (SOCS) 3 expression negated IL-6 and OSM effects and significantly reduced cellular apoB mRNA abundance. We conclude that IL-6 favors secretion of apoB-containing lipoproteins by increasing availability of apoB through changes in apob gene transcription. These changes may contribute to hypersecretion of VLDL associated with obesity, particularly under conditions where SOCS3 is not overexpressed to an extent capable of overcoming IL-6-stimulated apob gene transcription.