Recent data suggest that intake of more simple carbohydrates and less saturated fat is higher in patients with NAFLD compared with the general population, suggesting that dietary imbalances play a role in the development and progression of NAFLD (25
). The ideal diet for NAFLD should reduce fat mass and inflammation in the adipose tissue, restore insulin sensitivity, and provide low amounts of substrates for de-novo
), but scientific evidence to recommend specific diets is currently lacking. Although prior studies suggest an association between increased fructose consumption with NAFLD, no study to date has implicated a dietary risk factor in NAFLD progression. Defining modifiable risk factor(s) for liver disease progression in NAFLD would have significant public health implications for the development of strategies which may decrease risk for liver fibrosis and associated health-related complications. Evidence that childhood obesity and pediatric NALFD are becoming epidemic, particularly in young boys who tend to consume soft drinks (27
), suggests that there is a significant opportunity to improve risk factors for progressive liver damage at early stages of life.
In this study we investigated the impact of increased fructose consumption on the metabolic syndrome and histologic features of NAFLD. In patients with established NAFLD, increased consumption of fructose was associated with younger age, male gender, increased BMI, increased serum triglycerides, lower HDL cholesterol, and higher uric acid levels. To our surprise, increased fructose consumption appeared to improve systemic insulin sensitivity (i.e. lowered fasting serum glucose, slight decrease in serum insulin and HOMA-IR). Although this observation was diminished when excluding all subjects requiring insulin or insulin-sensitizing agents, this finding is particularly notable as it was observed despite evidence that daily fructose ingestion was accompanied by a significant increase in daily consumption of total calories, carbohydrates, proteins, and fats, as well as increased BMI. Further, based on our extended analysis, such associations still appeared to exist among subjects who were on insulin or insulin sensitizing agents (data are not shown). The limited sample size in the subgroup and the cross-sectional nature of this analysis limits the ability to draw any conclusions regarding causality and/or the impact of increased fructose consumption on the natural history of NAFLD. Further studies are required to delineate potential differential influences of fructose consumption on insulin sensitivity. Also, from the time of diagnosis of NAFLD to the time of study participation, patients may have spontaneously initiated life-style modification (ie. decreased sugar consumption, dietary modification, and/or increased exercise) which led to improved insulin sensitivity. Although, we attempted to decrease the window between liver biopsy and study participation to only 3 months, even a modest dietary change or weight loss could improve insulin sensitivity. Although a dose response relationship between fructose and low HDL cholesterol was observed, the apparent lack of a dose-response relationship between fructose intake and insulin resistance may potentially be explained by other confounders (ie. use of insulin sensitizing agents or lipid lowering agents) which may alter peripheral and/or hepatic insulin sensitivity and decrease hepatic steatosis.
Despite our inability to link increased fructose consumption to worsened insulin resistance, daily fructose consumption was associated with metabolic abnormalities that typically accompany insulin resistance, including lower HDL-cholesterol and higher serum uric acid, even after adjusting for age, gender, and BMI. In this regard, our findings reproduce other reports that have linked such metabolic derangements with increased consumption of fructose (4
). Moreover, after controlling for factors that have been shown to influence NAFLD (e.g., age, gender, BMI, Hispanic ethnicity, and total calorie intake), we found that increased fructose consumption was associated with decreased
hepatic steatosis and increased
fibrosis. When lipid parameters (triglycerides, HDL- and LDL cholesterol), uric acid, and HOMA-IR were incorporated into the analytical model, the association of increased fructose intake with decreased steatosis and increased fibrosis persisted. In addition, older subjects (age > 48 years old) with NAFLD who consumed increased amounts of fructose (> 7 servings/week) had increased lobular inflammation and ballooned hepatocytes. Other studies have also identified older age as an independent predictor of NAFLD severity (35
). Together with those data, our results raise the possibility that habitual ingestion of fructose exacerbates liver injury and promotes fibrosis progression in NAFLD. However, the research tools utilized to collect dietary fructose consumption do not allow us to ascertain whether or not some other dietary constituent for which fructose is simply a “marker” accounts for our findings.
The concept that excessive consumption of fructose might promote progression of NAFLD is biologically plausible given experimental evidence that high fructose corn syrup-55 (HFCS-55) increases ER stress, promotes activation of the stress-related kinase, Jun N-terminal Kinase (JNK), induces mitochondrial dysfunction, and increases apoptotic activity (36
) in liver cells. Further, a link between dietary fructose intake, gut-derived endotoxemia, toll-like receptor 4 and NAFLD has been suggested by the results of human and animal studies (17
). Mice fed water enriched with 30% fructose develop hepatic triglyceride accumulation, altered markers of insulin resistance, portal endotoxemia, and increased hepatic lipid peroxidation, MyD88, and TNF-alpha levels. Such data suggest that fructose-induced NAFLD or NASH associated with intestinal bacterial overgrowth and increased intestinal permeability, subsequently leading to an endotoxin-dependent activation of hepatic Kupffer cells (41
). As discussed subsequently, habitual fructose consumption may also lead to an unfavorable energy balance in the liver which enhances the susceptibility of hepatocytes to injury (42
The lipogenic and proinflammatory effects of fructose appear to be due to its unique metabolism, which involves a period of transient ATP depletion due to its rapid phosphorylation within the cell and from its unique ability among sugars to raise intracellular and serum uric acid. In experimental animals, lowering uric acid concentrations ameliorated features of the metabolic syndrome induced by fructose, including weight gain, hypertriglyceridemia, hyperinsulinemia and insulin resistance, and hypertension (34
). These findings were surprising, because most authorities had considered uric acid to be either biologically inert or an important antioxidant in the plasma (43
). However, uric acid was found to have numerous deleterious biologic functions. Uric acid stimulates both vascular smooth muscle cell proliferation and the release of chemotactic and inflammatory substances, induces monocyte chemotaxis, inhibits endothelial cell proliferation and migration and causes oxidative stress in adipocytes, which results in the impaired secretion of adiponectin (1
). Fructose-related reductions in hepatic ATP may also help to explain why we observed a relationship between chronic ingestion of fructose, hyperuricemia, and NAFLD severity in our patients. However, after adjusting for total calorie intake and other metabolic features, the association between increased fructose consumption and liver injury persisted suggesting that an alternative mechanism other than hyperuricemia may be involved.
During hepatic fructose metabolism, two molecules of ATP are consumed per each fructose molecule that is metabolized. The resultant ADP is then further degraded to AMP. The fate of this AMP, in turn, is dictated by the relative activities of two competing enzymes, AMP kinase (AMPK) and xanthine dehydrogenase. When AMPK is more active than xanthine dehydrogenase, AMP is “re-cycled” to restore hepatocyte ATP content. Conversely, when xanthine dehydrogenase is more active than AMPK, AMP is converted to uric acid, delaying recovery of hepatic ATP stores . Intravenous administration of fructose to healthy subjects increases blood levels of uric acid, the urinary excretion of urate and xanthine, and acutely reduces hepatic ATP (49
). Further, obese patients with NASH were less efficient than healthy controls at recovering from fructose-induced depletion of hepatic ATP stores (51
). Exercise, metformin, thiazolidinediones, and adiponectin (12
), all of which have been shown to improve NASH, activate AMPK. Together, these data support the concept that hepatic AMPK activity is relatively inhibited in NASH, rendering hepatocytes more vulnerable to ATP depletion when ATP is consumed during fructose metabolism. Hence, the presence of hyperuricemia may be a surrogate measure of chronic hepatic ATP depletion in habitual fructose consumers (55
). In addition, hyperuricemia has long been recognized as a marker of advanced liver disease (49
). More recently, multivariate analysis demonstrated that hyperuricemia is also an independent risk factor for NASH (57
). Thus, studies in animals and humans suggest a mechanism by which habitual fructose consumption promotes progression of liver damage by exacerbating underlying abnormalities in hepatic energy homeostasis. Impaired hepatic energy homeostasis (i.e., ATP depletion) may also explain the observed associations of increased fructose consumption with decreased steatosis and increased hepatic inflammation; inability to supply ATP for the triglyceride synthesis may fail to transform toxic free fatty acids to a safer form of lipids (i.e., triglycerides), constrain accumulated free fatty acids in the liver and exacerbate lipotoxicity.
Fructose Associated Hepatic ATP Depletion
Although further research is necessary to confirm these results and evaluate this hypothesis directly, data from the current cross-sectional analysis are exciting because they not only lend credence to this concept, but suggest both a novel biomarker (serum uric acid) and a modifiable risk factor (dietary fructose) for liver fibrosis in patients with NAFLD. Given the latter, well-designed prospective controlled dietary intervention studies are necessary to evaluate whether a low-fructose diet improves the metabolic disturbances associated with NAFLD, but also alters the natural history of NAFLD in those at risk of disease progression.