Diet-induced protection against lipopolysaccharide includes increased hepatic NO production

The host response to Gram-negative infection includes the elaboration of nu merous proinflammatory agents, including tumor necrosis factor alpha (TNF a lpha) and nitric oxide (NO). A component of the hepatic response to infecti on is an elevation in serum lipids, the so called "lipemia of sepsis," whic h results from the increased production of triglyceride (TG)-rich Lipoprote ins 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 lipoprotein s to protect against endotoxicity in rodent models of sepsis. Herein we rep ort the capacity of a high-fructose diet to protect against LPS, most Likel y by inducing high circulating levels of endogenous TO-rich Lipoproteins. T he protective phenotype included the increased production of NO by hepatic endothelial cells. Rats, made hypertriglyceridemic by fructose feeding, exp erienced decreased LPS-induced mortality (P < 0.03) and systemic TNF alpha levels (P < 0.05) as compared with normolipidemic (chow-fed) controls. The increased survival was associated with elevated levels of inducible NO synt hase (NOS2) mRNA levels and NO production (82 +/- 26 vs 3 +/- 3 nmol nitrit e/10(6) cells, P < 0.001) by hepatic endothelial cells. Nonselective NOS in hibitors 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 e ndotoxicity in part through induction of endogenous TG-rich lipoproteins an d hepatic endothelial cell NO production. This is the first report of diet- induced hyperlipoproteinemia and subsequent protection against endotoxemia. (C) 1999 Academic Press.