15 Dietary fructose is absorbed into the intestine by way of a saturable, facultative glucose transporter

(GLUT5). Healthy persons are able to absorb up to 25 g. Malabsorption can lead to increased fructose fermentation by gut bacteria.48 Findings regarding endotoxin (lipopolysaccharide [LPS]) NVP-AUY922 levels in portal blood in human NAFLD have been mixed, in part because portal blood is difficult to sample in human subjects and circulating levels are inconsistent. Normally, endotoxin released from the gut is cleared rapidly on first pass by Kupffer cells. However, a growing body of evidence supports a role for increased gut permeability and endotoxin in human NAFLD. In type II diabetes, endotoxin contributes to the development of the subclinical inflammatory state and insulin resistance by stimulating the innate immune system and inducing release of proinflammatory cytokines from adipose tissue. While HDL is known to neutralize LPS, this antiinflammatory function has been shown to be less effective in patients

with NAFLD.49 If HDL protection of LDL is decreased, that could lead to greater levels of oxidized LDL in NAFLD, which has previously been demonstrated.50, 51 Supporting this, in a small study of children with NAFLD, a low fructose diet resulted in diminished oxidized LDL.51 The relationship of fructose-induced endotoxin to disease in humans is even less well understood than the role of endotoxin find more in NAFLD; the direct relationships require further exploration. Limited studies suggest an association between fructose consumption and NAFLD. A pediatric study demonstrated increased carbohydrate intake in children with NAFLD identified by ultrasound compared to obese non-NAFLD counterparts.52 Small see more case-control studies of adults demonstrate higher

fructose and/or soft drink consumption in those with NAFLD.53-55 A study demonstrating excess soft drink consumption predicted NAFLD in a cohort of adults without typical risk factors for NAFLD lends support for a fructose effect independent of obesity.56 Abdelmalek et al.57 evaluated histologic features of a large cohort of adults with NAFLD and correlated this to estimated fructose intake. Although steatosis grade was lower in those with increased fructose intake, the degree of fibrosis was increased. In this same study, serum uric acid was substantially higher in those with increased fructose intake. Uric acid has been proposed as a biologic marker of fructose intake because uric acid levels increase with fructose intake.58, 59 In a large cohort of children with NAFLD, histopathology did not correlate with self-reported sugar consumption; however, uric acid was significantly increased in those with NASH compared to those with steatosis alone.60 It has been proposed that uric acid may mediate some of the abnormalities seen with fructose consumption through induction of retinol binding protein-4 (RBP-4), an adipokine linked to hepatic insulin resistance.