Extensive evidence from epidemiological, animal models and human data suggests that high fructose consumption has an important role in the development of hepatic steatosis and the progression to nonalcoholic steatohepatitis. The putative mechanisms linking fructose intake and nonalcoholic fatty liver disease (NAFLD) are reviewed here with an emphasis on the most recent findings.
NONALCOHOLIC FATTY LIVER DISEASE AND ’FATTY LIVER SYNDROME’
NAFLD encompasses a spectrum of disease that ranges from simple steatosis, to nonalcoholic steatohepatitis, to cirrhosis. Individuals with NAFLD typically have a clinical constellation of findings that we have termed ‘fatty liver syndrome’. Fatty liver syndrome consists of NAFLD plus visceral adiposity, dyslipidemia, insulin resistance and often acanthosis nigricans. Patients with NAFLD have increased risk of both cardiovascular disease and type II diabetes [1,2]. NAFLD is estimated to affect approximately 1 billion individuals worldwide, and its incidence and prevalence continue to increase globally . With the substantially rising trend of obesity and the current obesogenic environment , NAFLD is expected to rise to the level of a major public health crisis in the next few decades.
In particular, NAFLD in children is concerning because it appears to be an early, aggressive form of the disease. A natural history study with a 20-year follow-up indicated that children with NAFLD may develop end-stage liver disease with the consequent need for liver transplantation and may have a shorter survival as compared with the general population matched with age and sex . Given the fact that prevalence of pediatric NAFLD has more than doubled in the past 2 decades and currently affects approximately 11% of adolescents in the USA , children with NAFLD need effective treatment to prevent their lifelong risk for end-stage liver disease as well as other comorbidities.
UPDATED UNDERSTANDING OF NONALCOHOLIC FATTY LIVER DISEASE PATHOPHYSIOLOGY
NAFLD is defined as the presence of steatosis in the liver in the absence of significant alcohol consumption and other secondary causes of hepatic steatosis (medications, parenteral nutrition, hepatitis C, etc.). Steatosis is a critical defining feature of NAFLD but is not unique to NAFLD as other conditions also lead to increased lipid deposition in the liver including mitochondrial diseases, uncontrolled diabetes, starvation, and more. Steatosis occurs when the amount of triglyceride surpasses the normal metabolism capacities and abnormal storage results. The healthy liver contains less than 5% lipid by volume and amounts above this are almost always pathologic. In NAFLD, there is increased rate of hepatic triglyceride synthesis, because of increased fatty acid uptake and esterification into triglyceride along with higher de novo lipogenesis (DNL), exceeding the catabolic rate from fatty acid oxidation and ability to exportation as very low density lipoprotein (VLDL). A tracer study by Lambert et al.[7▪▪] recently showed that the primary difference in intrahepatic lipid flux between individuals with and without NAFLD is elevated DNL.
FRUCTOSE AND NONALCOHOLIC FATTY LIVER DISEASE – EVIDENCE FROM EPIDEMIOLOGICAL AND CLINICAL DATA
Because of the high level of consumption in the US diet and its interesting metabolic fate (discussed below), fructose has been studied in relation to many health problems, including NAFLD. Fructose was initially linked to steatosis and NAFLD in animal models but more recently, a number of human studies have examined and supported the relationship between high fructose intake and NAFLD. In a cross-sectional analysis, Ouyang et al. found a nearly two-fold to three-fold increase of fructose consumption in patients with biopsy-proven NAFLD as compared to their sex, age, and BMI-matched controls. Work by Abdelmalek et al. reported a significant association between fructose intake and fibrosis severity in a cohort of 427 adults with histologically confirmed NAFLD. Most recently, a longitudinal study [10▪] indicated that energy-adjusted fructose intake was independently associated with NAFLD in obese adolescents during a 3-year follow-up.
Findings from feeding trials have generated controversies over the role of fructose. Johnston et al. provided healthy but centrally overweight men with a high-fructose or high-glucose diet (25% energy) during an isocaloric period of 2 weeks and they reported neither fructose nor glucose induced significant changes in hepatic concentration of triglyceride or serum levels of liver enzymes. However, Cox et al. found that consumption of a similar amount (25% of energy requirements) of fructose- but not glucose-sweetened beverages for a longer term (10 weeks) significantly increased the liver enzyme gamma-glutamyltransferase activity and uric acid profile in overweight/obese individuals. Work by others feeding healthy volunteers with very-high-fructose or glucose diets for 4 weeks also observed an increase in plasma triglyceride specifically to fructose but not glucose . The task of testing the effect of fructose and NAFLD in clinical trials has been challenging, mostly because dietary manipulation in free living humans is full of variables and pitfalls. One of the areas of controversy in study design is whether the total caloric intake is hypercaloric or isocaloric. In the setting of hypercaloric, consuming fructose consistently increased both liver enzyme ALT and intrahepatic fat content, whereas there was no dominant effect of fructose in isocaloric trials . Two recent systemic reviews thus concluded that the apparent association between indexes of liver health and fructose or sucrose feeding appears to be confounded by excessive energy intake [14,15]. The studies included in these reviews had noted limitations including relatively small sample size (≤32) and most with a study duration of less than 4 weeks.
Two more recent trials reduced fructose intake and tested response. In a randomized controlled trial, 4 weeks of fructose restriction in children with NAFLD improved their adipose insulin sensitivity, high sensitivity C-reactive protein, and LDL oxidation, whereas their liver enzymes and intrahepatic fat remained unchanged compared with an eucaloric fructose fed group [16▪]. But over a longer intervention of 6 months, improvements of liver enzymes and insulin sensitivity were seen with lowering dietary component of fructose and glycemic load in NAFLD patients [17▪]. More interestingly, these improvements occurred in the absence of any changes in weight, BMI, or waist circumference and without any emphasis on dietary caloric restriction. Therefore, it appears that 6 months of improved dietary nutrient quality (e.g. lower fructose), without energy limitation or weight loss, leads to improved insulin resistance and liver health in individuals with NAFLD. From a public health standpoint, it is less important what mechanism of action drives the improvements seen with fructose reduction as there is little to no risk from reduction of fructose in the diet.
Studies of fructose and NAFLD also vary by the population studied and this is important because NAFLD is strongly genetic. Several polymorphisms have been identified as increasing susceptibility to NAFLD including one in the patatin like phospholipase containing domain 3 (PNPLA3) gene and glucokinase regulatory protein among others [18–20]. Hispanics in particular are at elevated risk because of their higher frequency of these genetic variants. There appears to be a gene–environment interplay between PNPLA3 and dietary sugaras shown in a study of overweight youth in which having both PNPLA3 variant and increased sugar intake was strongly associated with increased fraction of hepatic fat . In addition, patients with obesity or with NAFLD could be less tolerant of fructose because they already have deregulated lipid metabolism and they absorb and metabolize fructose more effectively than healthy lean controls [22▪▪]. We previously showed that children with NAFLD fed fructose as 33% of calories for 1 day exhibited exacerbated metabolic profile compared with non-NAFLD children .
FRUCTOSE AND NONALCOHOLIC FATTY LIVER DISEASE – A DIRECT LINK THROUGH INCREASE OF LIPOGENESIS
Increased DNL is a distinct characteristic of individuals with NAFLD and this could explain why dietary fructose is particularly harmful in NAFLD [7▪▪]. High fructose loads stimulate lipogenesis and can lead to an increased hepatic lipid burden . As a highly lipogenic sugar, fructose is efficiently metabolized via fructokinase in the liver and rapidly accumulates as fructose-1-phosphate in an insulin-independent fashion. Fructose-1-phosphate is then converted into triose phosphate that leads to high fluxes through the downstream steps of the glycolytic pathway, generating precursors and substrates for DNL. But fructose-induced lipogenesis is not mediated exclusively by the supply of excess substrates; as reviewed recently , it also appears to be a consequence of altered transcriptional regulation of lipogenic enzyme expressions including sterol regulatory element-binding protein 1 and carbohydrate-responsive element-binding protein. In addition, uric acid generated by fructose metabolism (usually in the hypercaloric setting) may also contribute to or exacerbate DNL and lipid disposition in hepatocytes by further activating fructokinase gene expression and causing mitochondrial stress .
Individuals who presented with elevated DNL during consumption of fructose-sweetened beverages also exhibited inhibition of postmeal lipid oxidation at the same time, suggesting that fructose may promote a net intrahepatic fat accumulation both directly via DNL and indirectly via DNL-induced inhibition of fatty acid oxidation . Interestingly, in a rat model, high fructose, if consumed with high fat diet, is likely to be more conductive to the development of liver steatosis . Crescenzo et al. compared high fructose high fat regimen to high fat alone and low fat diets; it was demonstrated in rats that high fructose high fat diet further promoted hepatic triglycerides content and severity of steatosis along with exacerbated dyslipidemia and insulin resistance. This could be attributable to increased hepatic fatty acid synthase activity (an important enzyme for lipogenesis) and decreased mitochondrial oxidative capacity. Future work in humans is warranted because high fructose-containing beverages are frequently consumed with the high fat meal in a typical Westernized meal.
RELATIONSHIP OF FRUCTOSE TO FEATURES OF FATTY LIVER SYNDROME
In addition to contributing directly to steatosis, fructose may interact with the systemic metabolic dysregulation associated with NAFLD.
Although fructose promotes hepatic DNL and causes lipid accumulation locally, the newly synthesized fatty acids are also packaged as VLDL to increase exportation into the circulation. Postheparin lipoprotein lipase activity is found to be lower with fructose consumption . Hepatic overproduction of large VLDL particles, combined with delayed clearance by lipoprotein lipase, create increased plasma triglycerides and concomitantly allow for augmented lipoprotein remodeling to generate small, dense LDL particles, thereby creating a proatherogenic environment. An intervention study by Stanhope et al. proved that these effects are fructose specific and not related to glucose (or carbohydrates in general) when they showed increased postprandial triglycerides, small dense LDL particles, oxidized LDL, and remnant-like particle lipoprotein-triglycerides in healthy adults consuming fructose- or HFCS-sweetened beverages for 2 weeks, but not in participants consuming glucose beverages .
Greater consumption of fructose is associated with increased visceral adiposity in both adults and children [29,30]. Human adipocytes, when cultured in growth media containing high fructose, develop lipid vesicles significantly earlier and have deregulated energy hemostasis [31▪▪]. Expanded visceral adipose tissue is metabolically active and produces numerous inflammatory cytokines (e.g. TNFα, IL-6) that foment insulin resistance . Insulin resistance in adipocytes fails to suppress the hormone-sensitive lipase, and results in elevated free fatty acids being delivered to the liver. The steatotic liver must then compensate for this overload of free fatty acid. Stanhope et al. demonstrated that consuming fructose-sweetened beverages for 8 weeks increased visceral adiposity.
As noted, NAFLD and insulin resistance are closely intertwined. An increase of metabolites from fructose to the hepatic lipid supply contributes to hepatic insulin resistance, possibly through increased intrahepatic level of diacylglycerol [33,34]. This lipid intermediate, diacylglycerol, can activate protein kinase Cε and inhibits the phosphorylation of insulin receptor substrate proteins, producing impaired downstream insulin signaling. Several lines of evidence have clearly indicated that hepatic insulin sensitivity is exquisitely sensitive to fructose intake [29,35], even in a relatively small amount (15% of baseline energy intake) and over a shorter duration (3 weeks) . The underlying mechanism(s) remain not fully elucidated but may involve a stimulation of glucogenesis and increased glycogen stores, or may be related to hepatic lipotoxicity.
Insulin resistance may preprogram the liver to develop NAFLD. A novel study in nonhuman primates demonstrated that diet-induced maternal insulin resistance was responsible for initiating dysregulation of hepatic immune system and development of de novo lipogenic pathways in their offspring, and these influences even might not be reversible upon switching to a healthy diet at weaning for 1 year [36▪▪]. These findings were further supported by a retrospective autopsy study examining the specific association between maternal diabetes and fetal hepatic steatosis [37▪▪]. Higher prevalence of hepatic steatosis was observed in fetus delivered by the diabetic mother. Patel et al. also reported a significant correlation between grade of fetal steatosis and gestational age, implying an incremental increase in hepatic fat with prolonged exposure to diabetic environment. These emerging lines of evidence are pivotal because they suggest that NAFLD risk is inextricably linked to our early life environment where maternal, fetal, and childhood factors may predict its risk later in life. To date, there remains a paucity of human data on the effects of dietary fructose intake during pregnancy and none that have examined long-term effects on the offspring. Evidence from an animal study , however, showed that fructose intake during pregnancy results in maternal hyperinsulinemia which may favor hepatic steatosis.
FRUCTOSE AND NONALCOHOLIC FATTY LIVER DISEASE – A CONNECTION THROUGH ALTERATION OF MICROBIOME
Recently, the role of the gut microbiome in the pathogenesis of NAFLD has gained attention. A series of studies  have demonstrated that patients with NAFLD have an altered intestinal microbiota as compared with healthy lean or obese individuals. Increased intestinal permeability and disruption of the mucosal barrier are required for microbial products translocation from the lumen to extraintestinal space. In patients with NAFLD, lactulose/mannitol ratio, an indicator of intestinal permeability, is found to be significantly increased, and it also tightly correlates with the severity of the disease [40▪]. Tight junction protein occudin is also lower in duodenal biopsy specimens . A leaky gut seen in NAFLD thus contributes to elevated lipopolysaccharide (LPS, also known as endotoxin), which has been shown to stimulate the innate immune system via Toll-like receptor 4 and to trigger inflammatory pathways, in turn, causing liver injury.
Fructose is absorbed in the small intestine primarily through glucose transporter family and malabsorption occurs commonly at the level above 50 g, which is well below the US average intake . Malabsorbed fructose would pass on to the colon and interact with bacteria there. Early work in mice demonstrated that fructose increased intestinal translocation of bacterial endotoxin and subsequent activation of Kupffer cells through Toll-like receptor-dependent mechanisms, leading to hepatic steatosis. Improving endotoxin levels by administration of antibiotics decreased fructose-induced hepatic steatosis . Our group published work [43▪] showing that children with NAFLD had higher levels of circulating endotoxin, and this correlation persisted even after adjusting for BMI, insulin resistance, and inflammatory marker high sensitivity C-reactive protein. Furthermore, we found that high-fructose ingestion stimulated circulating endotoxin levels in both acute and relatively chronic fashions in children with NAFLD. Individuals with NAFLD, comparing with healthy controls, exhibited significantly increased postprandial endotoxin levels after consuming high-fructose-containing beverages with meals within just 1 day. A 4-week continuation on fructose-containing drinks had prolonged effect on endotoxin elevation, whereas this effect was not seen in children with NAFLD consuming glucose-containing drinks alternatively.
Excessive fructose intake plays a multifaceted role in favoring the pathogenesis of NAFLD, including stimulating hepatic lipogenesis, increasing visceral adiposity, and altering the gut microbiome (Fig. 1). Fructose consumption is still much higher than the recommended levels and restriction may be particularly important for individuals at risk of NAFLD or who have NAFLD. What dose of fructose consumption is well tolerated with respect to NAFLD is not known and may vary by risk factors. Further research is also needed on the role of fructose restriction in NAFLD prevention, particularly during the vulnerable in utero and early life time periods.
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Conflicts of interest
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REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
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