Diet-induced protection against lipopolysaccharide includes increased hepatic NO production

The host response to Gram-negative infection includes the elaboration of numerous proinflammatory agents, including tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO). A component of the hepatic response to infection is an elevation in serum lipids, the so-called "lipemia of sepsis," which results from the increased production of triglyceride (TG)-rich lipoproteins by the liver. We have postulated that these lipoproteins are components of a nonadaptive, innate immune response to endotoxin [lipopolysaccharide (LPS)] and have previously demonstrated the capacity of TG-rich lipoproteins to protect against endotoxicity in rodent models of sepsis. Herein we report the capacity of a high-fructose diet to protect against LPS, most likely by inducing high circulating levels of endogenous TG-rich lipoproteins. The protective phenotype included the increased production of NO by hepatic endothelial cells. Rats, made hypertriglyceridemic by fructose feeding, experienced decreased LPS-induced mortality (P < 0.03) and systemic TNFalpha levels (P < 0.05) as compared with normolipidemic (chow-fed) controls. The increased survival was associated with elevated levels of inducible NO synthase (NOS2) mRNA levels and NO production (82 +/- 26 vs 3 +/- 3 nmol nitrite/10(6) cells, P < 0.001) by hepatic endothelial cells. Nonselective NOS inhibitors reversed the protective phenotype in vivo and readily decreased NO production by cultured endothelial cells from hypertriglyceridemic rats in vitro. This study suggests that a high-fructose diet can protect against endotoxicity in part through induction of endogenous TG-rich lipoproteins and hepatic endothelial cell NO production. This is the first report of diet-induced hyperlipoproteinemia and subsequent protection against endotoxemia.