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Noninvasive assessment of liver disease severity with liver fat score and CK‐18 in NAFLD: Prognostic value of liver fat equation goes beyond hepatic fat estimation
Author(s) -
Musso Giovanni,
Gambino Roberto,
Durazzo Marilena,
Cassader Maurizio
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23255
Subject(s) - medicine , nonalcoholic fatty liver disease , insulin resistance , endocrinology , steatosis , fatty liver , postprandial , steatohepatitis , liver biopsy , metabolic syndrome , insulin , gastroenterology , disease , obesity , biopsy
fructose exclusively caused the restoration of the significantly increased levels of these two parameters. These results clearly suggest that the presence of TLR-4 is essential to explain liver damage, body weight gain, and ALT impairment due to the fructose intake. Furthermore, the authors found that plasma endotoxin levels were significantly increased both in wild-type and mutant mice fed chronically with a 30% fructose solution, in comparison to water-fed controls. The role of fructose in NAFLD development was not entirely unknown to researchers. In particular, a recent work4 demonstrates that patients with NAFLD have a significantly greater consumption of fructose than controls, and an increased hepatic expression of fructokinase messenger RNA. Although the role of TLR-4 in carbohydratedependent NAFLD has been only recently suggested by Thuy and colleagues,5 they have pinpointed one of the potential mechanisms through which fructose could participate in NAFLD development and progression in humans: a carbohydrate-rich diet may produce ethanol when intestinal stasis favors bacterial overgrowth in the upper parts of the gastrointestinal tract. The increased portal endotoxemia could initiate TLR signaling and induce necroinflammation, which characterizes steatohepatitis, the most advanced form of NAFLD. Accordingly, this study also highlighted significant correlations between hepatic expression of TLR-4, plasminogen activator inhibitor 1, and endotoxin, even though they are still unable to explain the molecular signaling pathways. Interestingly, another recent study investigated the potential importance of Kupffer cells and TLR-4 in the pathogenic mechanisms underlying nonalcoholic steatohepatitis induced by a methionine-deficient and choline-deficient diet.6 Unfortunately, the study by Spruss et al. does not provide additional clues to the mechanisms by which fructose intake, endoxemia, and the resulting activation of TLR-4 signaling might promote NAFLD. On the other hand, the experimental results in this work allow the exclusion of the involvement of some important TLR-4 – dependent proinflammatory inducing transcriptional factors (i.e., IRF3 and IF37), suggesting that fructose feeding may lead to NAFLD through an insulin-independent de novo lipogenesis and/or an endotoxin-dependent activation of Kupffer cells. In this last hypothesis, an interaction network which involves TLR-4, Myd88, c-Jun N-terminal kinase, and nuclear factor B might induce tumor necrosis factor-alpha production and release, oxidative stress, and insulin resistance.7 We believe that although Spruss et al. present a well-conducted study, the precise role of TLR-4–dependent pathways in NAFLD requires further experimentation. In fact, it is possible that new additional signaling proteins of innate immunity, as yet uncovered, may be involved in the necroinflammatory process and in the progression to steatohepatitis and fibrosis.