Nonalcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver disease in many countries, and its prevalence is increasing. NAFLD is often considered to be a hepatic component of metabolic syndrome, and studies have established that insulin resistance plays a major role in the pathogenesis of NAFLD. Treatments for NAFLD primarily target insulin resistance. Interestingly, the most common environmental cause of insulin resistance is diet. This article examines the correlations between NAFLD and diet and provides some diet recommendations based on the most current data available.

Introduction

N onalcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver disease worldwide. The disease was first described as ‘‘nutritional liver disease’’ in the 1960s.1 NAFLD defines cases where more than 5% of liver weight consists of fat, despite the absence of significant alcohol consumption (less than 20 g/day).2 NAFLD is currently the most common liver disease, and it has been accepted as the hepatic component of metabolic syndrome.3–5 Therapy for NAFLD involves lifestyle modifications and treatment for insulin resistance. Diet has a key role in the etiology of NAFLD. In the present article, we examine correlations between diet and NAFLD and discuss recent developments in the field.

Diet in NAFLD Pathogenesis

Although the pathophysiology of NAFLD has not been completely clarified, the most valid hypothesis to date is the two-hit hypothesis, which was suggested by Day and James.6 According to this hypothesis, the initial hit results in steatosis, and changes from this hit make the liver susceptible to a second hit, which results in an inflammatory process and the development of nonalcoholic steatohepatitis (NASH). The increased fat accumulation in the initial hit is primarily caused by insulin resistance. Moreover, insulin resistance and subsequent hyperinsulinemia may be responsible for both hits. Interestingly, many studies have observed impaired fasting glucose or impaired glucose tolerance in patients with NAFLD.5,7–12

Overnutrition or inappropriate diet may lead to type 2 diabetes, which can cause hyperglycemia and increased insulin level. Increased insulin level has been shown to correlate with time, glucose uptake in adipose tissue, and decreases in skeletal muscle.13–15 Glucose uptake in the liver, however, is not insulin dependent, and increased glucose concentrations in the blood lead to increased glucose uptake by the liver.16 Glycogen synthesis that exceeds the capacity of the liver and insulin-mediated stimulation of de novo lipogenesis both lead to an increased conversion of glucose to fatty acids.17 As a result, increased blood glucose and free fatty acids cause a high amount of neutral fatty acid accumulation in the liver and microvesicular and macrovesicular fatty changes. In healthy individuals, elevated lipid concentrations in the liver lead to increased very-low-density lipoprotein (VLDL) production and secretion. In NAFLD patients, however, this increase in fat export via VLDL may be impaired or insufficient to prevent fatty liver.18

Macronutrients

Although insulin resistance plays a major role in the pathogenesis of NAFLD, the macronutrient composition of the diet has also been suggested to be very important (even more than the total calories). Thus, intake of fat, carbohydrates and protein should be examined separately.

Fatty acids

Irrespective of total calorie intake, the amount of fat and the chemical properties of the fat in the diet are important for individuals with fatty liver. Human and animal studies have shown that high-fat diets, despite being isocaloric, increased the amount of intrahepatic triglycerides (IHTGs).19,20 Injuries caused by free fatty acids (FFAs), especially saturated fatty acids (SFAs), are more important. In an animal study, SFAs were shown to cause hepatocyte damage by increasing endoplasmic reticulum stress.21 On the basis of clinical evidence, studies concluded that SFA intake of less than 7% of total fats and energy intake of more than 10% of total caloric intake may be suboptimal for NASH patients.22

Interestingly, monounsaturated fatty acids (MUFAs) can have positive cardiovascular effects. Monounsaturated fatty acids have also been shown to decrease oxidized low-density lipoprotein (LDL), LDL cholesterol (LDL-C), total cholesterol (TC), and triacylglycerol concentrations without reducing the high-density lipoprotein cholesterol (HDL-C) level.23–26 In addition, the replacement of carbohydrates and saturated fats with MUFAs in patients with diabetes leads to reductions in glucose and blood pressure and an increase in HDL.27 Moreover, increasing the ratio of MUFAs in the diet may also be beneficial for individuals with NAFLD. Hazelnuts and walnuts are good examples of foods rich in MUFAs and vitamin E that could be included in the diets of individuals with NAFLD.

Polyunsaturated fatty acids (PUFAs) contain n-3 and n-6 fatty acids, and the ratio of both is important. Indeed, prospective studies of patients with NAFLD showed that consumption of n-6 fatty acids and the ratio of n-6/n-3 fatty acids were elevated compared with controls. In addition, these studies showed that consumption of n-3 fatty acids had potential benefits for NAFLD patients.28–33

Musso et al. have shown that patients with NASH consumed more saturated fat and lower polyunsaturated fat compared to controls. Furthermore, they demonstrated that postprandial total cholesterol, VLDL, and triglycerides are more increased than controls.34

Trans-fatty acids are unsaturated fatty acids with at least one double bond in the trans configuration. Although trans-fatty acids are rarely found in natural foods, they are formed during the production of partially hydrogenated oils.35 Although recent animal studies have shown that the addition of some trans-fatty acids to a low-fat diet resulted in similar or increased IHTGs, studies have not shown whether trans-fatty acids cause increased IHTGs in humans.36,37 Other diseases, however, such as insulin resistance, cardiovascular disease, and diabetes, have shown correlations between humans and animal. Thus, trans-fatty acids should be avoided in individuals with NAFLD.38

Glycemic index

The consumption of high-glycemic-index foods has been associated with obesity and insulin resistance.39 Valtuena et al.40 observed a close relationship between the degree of hepatosteatosis and the dietary glycemic index, which was independent of the total energy or carbohydrate intake. Compared with rats fed a low-glycemic-index diet, rats fed a high-glycemic- index diet showed a significant increase in body fat mass without any change in total body weight.41 Hepatic de novo lipogenesis occurs when rapid and intensive glucose accumulation, which is caused by excessive consumption of high-glycemic-index foods, exceeds the glycogen synthesis capacity in the liver.20,42–44 Low-glycemic-index carbohydrates (complex carbohydrates) only induce a slight increase in blood glucose, which results in a low insulin response.

Carbohydrates and fructose

Carbohydrate consumption also plays a role in the pathogenesis of NAFLD. The main dietary carbohydrates are glucose, sucrose, and fructose. Sucrose is a disaccharide that consists of a combination of glucose and sucrose. Fructose is metabolized in the liver and plays an important role in the pathogenesis of NAFLD. Fructose, which is less responsive to insulin compared with glucose and sucrose, has been considered to be more lipogenic.45 Furthermore, fructose bypasses the rate-limiting step in glycolysis, which is catalyzed by phosphofructokinase, and this results in a lack of control over fructose metabolism. In recent years, the food industry replaced sucrose, which is a refined sugar, with high-fructose corn syrup (HFCS) (containing 42%–90% fructose). Consumption of high-fructose corn syrup has been increasing gradually throughout the world because of its use in soft drinks. Although recent studies of NAFLD patients did not find a significant difference in total carbohydrate consumption compared with controls, fructose consumption was significantly higher in the NAFLD group.46–48 Moreover, Abid et al. have shown that increased soft drink consumption, independently from metabolic syndrome, is a strong predictor of NAFLD.48 In a study including 427 NAFLD patients reported by Abdelmalek et al., daily fructose consumption was associated with hepatic inflammation and ballooning as well as fibrosis.49 In addition, studies in rats have shown that soft drinks increase hepatic de novo lipogenesis, hypertriglyceridemia, and hepatic insulin resistance and cause hepatosteatosis.50 Moreover, soft drinks have also been shown to cause similar effects in humans.51,52 Animal models have suggested that fructose induces peroxisome proliferator-activated receptor gamma coactivator 1 beta, sterol regulatory element-binding protein 1c (SREBP-1c), and carbohydrate response element-binding protein (ChREBP).53,54 Both SREBP-1c and ChREBP are transcription factors for proteins involved in lipogenesis, and their upregulation by fructose may increase de novo lipogenesis, which contributes to IHTGs.43 In light of these studies, we recommend that fructose consumption should be restricted in individuals with NAFLD.

Proteins

There are several studies addressing the role of proteins in the pathogenesis of NAFLD and NASH, and protein deficiency and malnutrition are known to predispose individuals to NASH. In addition, studies have demonstrated that the consumption of high amounts of red meat causes insulin resistance, increased diabetes frequency, and increased risk of cardiovascular disease.55–57 Negative effects of protein deficiency, however, have also been shown, and the value for the upper limit of protein intake remains unclear.

Vitamins

Recent studies have found associations between vitamin D deficiency, increased insulin resistance, and NAFLD among children.58 In a study conducted by Targher et al., it was shown that the level of 25-hydroxy vitamin D is lower than healthy controls, and this low level is associated with histopathological features of NAFLD patients.59 However, in a recently reported large study including 1,630 adolescents, no association was found between low vitamin D and probable NAFLD.60

There are some recent studies investigating effect of antioxidant vitamin E on NAFLD. Lavine et al. have showed that there is improvement in transaminases in juvenile patients with NASH when given 400–1200 IU of vitamin E daily.61 In a randomized, placebo-controlled, and double-blind study reported by Harrison et al.,45 patients with NASH were given a low-fat diet (<30 grams/day fat) and vitamin E and vitamin C (1,000 IU/day and 1,000 mg/day, respectively) for 6 months.62 At the end of the study, there was no change in levels of transaminase and hepatic necroinflammation with this treatment, but there was a significant improvement in fibrosis levels. In the study by Nobili et al., treatment with vitamin E and vitamin C (600 IU/day and 500 mg/day, respectively) for 1 year did not show any additive effect on the improvement that was gained with weight reduction by diet and physical exercise.63 Finally, in the study reported by Sanyal et al. including 247 patients with NASH, daily 800 IU vitamin E treatment for 96 weeks had positive effects on hepatic steatosis and lobular inflammation, but the effect of this treatment on fibrosis was not superior to the placebo.64 On the other hand, another study showed that patients with NASH consumed less vitamin C and vitamin E compared to controls.34 In conclusion, because there are contradictory results about vitamins in the studies conducted on patients with NASH, there is a need for large comprehensive studies on this issue.

Effects of Diet on NAFLD

Currently, there is no valid medical therapy available for NAFLD and NASH. Although there are several drugs with established effects, the long-term results of these drugs are unknown. Lifestyle modification is still the most valid therapy for NAFLD when insulin resistance is the primary cause of NAFLD pathogenesis. These modifications include diet modification, limiting caloric intake, increased physical activity, or a combination of all these elements. Indeed, many recent studies have shown the therapeutic efficacy of diet and exercise.

Compared with individuals without hepatosteatosis, patients with NAFLD have a higher caloric intake.65 Although limiting calories is an accepted therapy, calories should be limited moderately because prolonged fasting, hypocaloric diet (<500 kcal/day), and jejunoileal bypass surgery aggravate hepatosteatosis.66 Interestingly, in addition to weight loss, gastric band and bypass studies resulted in improvements in steatosis, inflammation, and fibrosis.67–69 Moreover, recent studies have shown that moderate weight loss resulted in improvements in both transaminase levels and liver histology.22,70–72

Westerbacka et al.19 studied the effects of various amounts of dietary fat on hepatosteatosis using magnetic resonance proton spectroscopy. They compared groups of nondiabetic obese women who received a low-fat (16% of total energy) or a high-fat (56% of total energy) diet for 2 weeks (the diets were isocaloric). Although the initial liver-to-fat ratio was 10%, this ratio decreased to 8% in the low-fat-diet group, but increased to 13.5% in the high-fat-diet group. Interestingly, another obesity study compared a low-fat diet with a low-carbohydrate diet and found that the low-carbohydrate diet was more accepted by patients and resulted in greater weight loss.73

In addition, Huang et al.74 put 15 patients with biopsy-proven NASH on a diet for 1 year [40% carbohydrates/fiber, 35%–40% fat (also unsaturated) and 15%–20% protein] before performing a second liver biopsy. They found that the average weight loss was only 2.9 kg; however, 9 out of 15 patients showed histological improvement. These results show that even a slight weight loss can be beneficial.

Effects of Lifestyle Modification

Currently, the most valid therapy for NAFLD is lifestyle modification. Weight loss, increased muscle mass, increased peripheral insulin sensitivity, and improvement in lipid profile are targeted with a combination of increased physical activity and diet modification. In addition, studies have shown the positive effects of this approach on metabolic syndrome and cardiovascular risk.75,76 Interestingly, one study showed that walking 2 miles for 3 days a week at a target heart rate of 60% of heart rate reserve (as measured by peak oxygen uptake) increased HDL and was equivalent to a more rigorous exercise program of walking 3 miles for 3 days a week at 80% of heart rate reserve.77 Moreover, studies involving a combination of diet and exercise have shown a significant decrease in transaminase levels.78–81 Even without successful weight loss, exercise appeared to improve transaminase levels. Thomas et al.82 studied 10 patients using magnetic resonance imaging and showed that a reduction of 500 kcal in total calorie intake and increased physical activity for 6 months decreased intrahepatocellular lipids (IHCLs) by 40%.

Conclusion

The etiology of NAFLD, which is the most common chronic liver disease, is multifactorial. Although the pathogenesis is unclear, the underlying mechanism is insulin resistance, which is why the disease has been considered to be a component of metabolic syndrome. No efficient medical therapy is currently available for NAFLD, and it seems that the most valid therapeutic modality is probably lifestyle modification. To date, however, there are only a limited number of studies on this issue.

In conclusion, individuals with NAFLD should decrease their daily caloric intake and limit their intake of saturated fats, trans-fatty acids, monosaccharides, and especially high-fructose corn syrup. Therapy should include diet modifications and should aim to ensure moderate weight loss with increased physical activity. This approach will decrease adipose tissue, which acts as an endocrine organ. Future studies should provide a clearer understanding of the pathogenesis of NAFLD, and, combined with the data that will be obtained with randomized controlled studies, we will be able to make more concrete diet and therapy recommendations in the future.

Author Disclosure Statement

No competing financial interests exist.