© 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(13)60021-1

 

 

 

KEY WORDS: non-alcoholic fatty liver disease; therapy; pharmaceuticals; exercise

 

In the past decades, non-alcoholic fatty liver disease (NAFLD) has become one of the leading chronic liver diseases worldwide. The estimated prevalence of NAFLD in adult population is around 15%-30%, which increases with age.^[1-3] In the affluent regions of China, the community prevalence of NAFLD is approximately 15%.^[4] Since NAFLD is a risk factor of cirrhosis and even hepatocellular carcinoma, developing effective therapies with minimal side-effects against NAFLD is vital for controlling the progression of this disease to advance to end-stage liver disease.^[5] In the past, the term "NAFLD" includes a wide spectrum of chronic liver diseases, which ranges from simple steatosis (fat accumulation in the liver without inflammation and/or fibrosis) to non-alcoholic steatohepatitis (NASH; fat deposition with inflammation and/or fibrosis) and cirrhosis.^[6] This view has been recently challenged by a multiple parallel hit hypothesis of NAFLD, in which steatosis and NASH are discrete entities rather than two points of the NAFLD spectrum, not only from a set of histological criteria but also from a pathophysiological standpoint.^{[7, 8]} To date, the detailed pathogenic mechanism of NAFLD including steatosis and NASH is not fully characterized, although it is regarded as a hepatic manifestation of the metabolic syndrome^[9] or sometimes it occurs in the absence of metabolic syndrome.^[10] Thus, uncontrolled NAFLD-induced injury may further influence other body systems, such as the cardiovascular system, kidneys and pancreas, to cause hyperlipidemia, hypertension, type 2 diabetes, pancreatitis, and atherosclerosis.^[11-15] Based on conventional models of "two-hit" and "multi-hit" hypothesis of NAFLD, in which the dysregulated lipid metabolism and insulin resistance are considered as the "first hit" of the liver and the following "second hit" or "multi-hit" likely involves oxidative stress, lipid peroxidation, increased inflammatory responses, induced hepatic fibrosis and apoptosis,^{[16, 17]} recent "multiple parallel hits" model emphasizes the multi-factorial pathogenesis of NAFLD and the necessity to treat NAFLD with diabetes-like and multimodal strategy.^[7] Excessive free fatty acids (FFAs), either produced from excessive de novo hepatic lipogenesis or from overloaded consumption of carbohydrate, play a central role in inducing lipotoxicity and following insulin resistance.^[18] Impaired insulin signaling system is responsible for the occurrence of lipid peroxidation and oxidative stress which cause downstream necro-inflammation and apoptosis through transcription factors- and kinase-dependent pathways.^[19] Therefore, therapies targeted for aforementioned key events during NAFLD development are tested to retard or ameliorate the chronic liver injury at different levels. Currently, there are two major categories of NAFLD therapy namely: lifestyle interventions and pharmaceutical therapies.

 

 

Nowadays it is clear that obesity is associated with the increased risk of NAFLD. It has become a major health burden in the present century. In the USA, more than one-fourth people are obese and three-fourth of them have fatty liver disease.^[20] For patients with body mass index (BMI) >35 kg/m², bariatric surgery is the only effective therapy for morbid obesity.^[21] The phenotype of obesity is connected with increased intra-abdominal fat (e.g. visceral adipose). Since visceral adipose holds more lipolytic capability than subcutaneous adipose on a per-unit-mass basis, FFAs released from visceral fat may get into the portal vein and caused a "first-pass" effect on the liver, indicating that the liver is exposed more FFAs than the peripheral tissues, especially in patients with visceral obesity.^[22] Also, the increased concentration of FFAs is taken into account as a major aspect in the development of insulin resistance. Thus, the development of NAFLD is expected to be initiated by the increased obesity index and generation of insulin resistance, which is why the maintenance or reduction of weight is a key factor in the prevention of NAFLD progression. It is also an essential therapy for obese patients who have metabolic disease with features of NAFLD. Although weight loss decreases intra-hepatic fat content and improves metabolic function in young and middle-aged obese adults, the effects of weight reduction are controversial in the elderly.^[23] Generally speaking, increase in life expectancy from intentional weight loss could be achieved mainly in elderly patients with diabetes.^[24] However, since reduction of BMI with age frequently involves loss of muscle rather than fat tissue, waist circumference is a better indicator for elderly patients with obesity than BMI.^[25] In addition, it is noted that sometimes weight loss in elderly patients is unintentional, which is probably from pathological reasons such as cancers and cardiovascular diseases.^[26] Thus, the therapeutic benefit of weight loss in NAFLD needs further investigations, particularly in different ethnic groups and ages.

 

Current data clearly suggest that the level of energy intake is significantly higher in NAFLD patients than in individuals with no evidence of fatty liver.^[27] High-fructose diet in humans is related to the occurrence of obesity, metabolic syndrome and NAFLD with increased energy intake level, fat mass and blood pressure.^[28] Thus, it is logical that reducing the dietary carbohydrate or energy content is beneficial for the retardation of NAFLD progression. Low (800-1800 kCal/day) and very low-calorie diets (<800 kCal/day) and/or carbohydrate restriction (20-50 g/day) significantly reduce body weight and intrahepatic lipid content.^[29] Another small retrospective cohort study of obese patients demonstrated that a 600-800 kCal/day diet for a mean of 16 months resulted in improvement of liver enzymes and hepatosplenomegaly.^[30] Petersen et al^[31] found that a low fat (3%) reduced calorie (daily intake 1200 kCal/day) diet effectively reduces body weight and intra-hepatic lipid content with improvement of insulin resistance in NAFLD patients. Thoma et al^[32] also illustrated that a range of lifestyle modifications exert very positive influence on reducing intrahepatic lipid contents and circulating enzyme levels, which lead to improved measures of glucose control and/or insulin sensitivity in patients with NAFLD. In the USA, more than one-fourth men and one-third women are trying to lose weight by lifestyle changes.^[33] Considering the close link between obesity and NAFLD, all patients who exhibit NAFLD symptom should be encouraged to continue moderate intensity of aerobic exercise and to take low-fat diet.^[34]

 

The convincing evidence of physical exercise on NAFLD treatment has been demonstrated by the reduction of liver lipid contents. A study investigating the effects of exercise on humans found that 9-day exercise training program increased lipid metabolism gene expression in skeletal muscle.^[35] A new study also proved that regular exercise (more than 3 times per week, at least for 30 minutes each time and for consecutive 3 months) was related to reduced risk of NAFLD and decreased liver enzymes in NAFLD patients independent of obesity in Korea.^[36] Another study prescribing 3-month moderate intensity exercise for NAFLD patients observed a 50% reduction in aminotransferase levels.^[37] However, evident beneficial effects can only be seen in NAFLD individuals who perform ≥150 minutes of aerobic type exercise per week.^[38] Furthermore, the mechanism for the direct hepatic benefit of chronic exercise training remains unclear.^[39] Since exercise has been shown to control the progression of fatty liver by reducing intrahepatic fat, fatty acid uptake and improving insulin sensitivity, it is proposed that exercise releases the burden of oxidative stress and inflammation caused by fat accumulation in the liver.^[40] A very recent study found that exercise training drastically attenuates hepatic inflammation, fibrosis and macrophage infiltration during diet induced-obesity in obese mice, indicating the positive effects of exercise on both steatosis and NASH.^[41] Interestingly, a recent well-designed randomized controlled trial tested the effects of lifestyle intervention using a combination of diet, exercise, and behavior modification. They found that after 48 weeks of intervention, the testing group lost an average of 9.3% of their weight versus 0.2% in the intervention-free group. They also significantly reduced their NAFLD activity score, indicating that combined intervention for a long-term therapy is effective for improving NAFLD histology.^[42]

 

In addition, the finding that exercise requires hepatic glucagon receptor activation to lower hepatic fat content is a step toward understanding the benefits of regular exercise. Several experiments provided mechanistic insight into the understanding on how repeated bouts of exercise-stimulated hepatic glucagon action lower the hepatic fat content.^[43-45] Post exercise findings in gcgr+/+ (glucagon receptor null) mice showed lowered hepatic energy state, increased AMPK activity, and elevated expression of AMPK-α1/-α2, PPAR-α, and FGF21 when compared with control and wild-type mice.^[44] AMPK, PPAR-α, and FGF21 are targets of hepatic glucagon action and key proteins involved in oxidative metabolism. Stimulation of these interrelated pathways suggested that repeated bouts of exercise-stimulated hepatic glucagon action heighten fat oxidation. Thus, consuming high-fat diet in mice provokes rapid and progressive fatty liver that is reversible by exercise in a glucagon receptor-dependent manner.

 

 

Induced by lipotoxicity from excessive FFAs, the level of reactive oxygen species and reactive nitrogen species may exceed the intracellular neutralizing ability of antioxidant enzymes, leading to the formation of oxidative stress. It is now clear that oxidative stress not only directly causes liver injury, but also induces other pathological events contributing to NAFLD progression, including inflammation, chemoattraction, necrosis, and apoptosis.^[46] Thus, several kinds of antioxidant therapy have been introduced to control the level of oxidative stress in NAFLD. A pilot study using combined therapy of lifestyle modification and vitamin E found that increased levels of liver enzymes, cholesterol, and plasma hyaluronic acid were significantly alleviated by the therapy. However, dysregulated level of cytokines was not re-balanced.^[47] Another prospective, double-blind, placebo-controlled trial in NAFLD patients found vitamin C and/or vitamin E treatment improved hepatic fibrosis, but not necro-inflammation and ALT levels.^[48] Conversely, a pilot study conducted by Lavine pointed out longer administration of vitamin E (4-10 months) markedly reduced serum ALT and AST levels without affecting BMI.^[49] Some reports indicated the safety of long-term use of vitamin E. A meta-analysis study showed that high-dosage vitamin E supplementation (≥?400 IU/d) may increase all-causes of mortality.^[50]

 

In addition to vitamins, herbal derivatives with antioxidant property are another promising therapy because 1) some common herbs (e.g. red grape, garlic, and green tea) are popular daily foods or food supplements that are easy to obtain; 2) adverse effect of herbal derivatives when administered in low dosage is usually very low or nil; and 3) several herbal derivatives are proven with high-efficacy in improving NAFLD parameters.^[51] Although detailed protective mechanisms of several herbal derivatives have been elucidated in animal models, the clinical application is still on the way. Among many derivatives, resveratrol from red grape received most attentions since it shows protective effects against many diseases, including NAFLD, cardiovascular diseases, diabetes and cancer.^[52] In animal studies, treatment of resveratrol attenuates NAFLD symptoms through inhibition of lipid peroxidation and inflammatory responses, as well as activation of LKB1/AMPK and Sirt1 pathways.^[53-56] Green tea extract is also tested in different NAFLD models, including in vitro models, cultured cells, tissue models, and in vivo models. Administration of green tea extract is shown to effectively ameliorate histological changes, fibrosis, oxidative stress, lipid accumulation, and inflammation occurred during NAFLD development.^[57-60] In addition, epidemiological data have shown that consumption of green tea lowers lipid dysregulation, serum ALT level, and the risk of cardiovascular disorders.^{[61, 62]} We recently identified the beneficial effects of S-allylmercaptocysteine, a water-soluble monomer from garlic, on NAFLD rat model. Addition of S-allylmercaptocysteine during a high-fat diet induction of NAFLD in rat reduces liver injury, including necro-inflammation, oxidative stress, and apoptosis. It also attenuates fibrosis and reduces dysregulated of lipid metabolism by modulating the kinase- and transcription factor-dependent pathways.^[63]

 

Since insulin resistance is one of the major triggering mechanisms for NAFLD progression, sensitization of insulin in patients with fatty liver disease receives increasing attention because it restores the ability of insulin to lower hyperinsulinemia and hyperlipidemia in peripheral adipocytes.^[64] Metformin and thiazolidinediones (TZDs, including pioglitazone and rosiglitazone) are major classes of insulin sensitizers applied in clinical studies.^[65] In early reports, rosiglitazone was demonstrated to normalize transaminases levels, inflammatory responses and hepatic steatosis.^[66-68] However, due to its obvious side effects (e.g. increase risk of heart attack), the use of rosiglitazone has been highly restricted in the USA and banned in Europe.^{[69, 70]} In a large controlled trial, when pioglitazone was taken with high fat diet in NAFLD patients, insulin sensitivity, serum ALT, steatosis, necro-inflammation but not fibrosis were significantly ameliorated when compared with high fat diet plus placebo control.^[71] Another placebo-controlled trial called PIVENS (pioglitazone versus vitamin E versus placebo) also found the beneficial properties of pioglitazone in improving hepatic histology, inflammation, and steatosis in non-diabetic NAFLD patients after 96-week administration.^[72] Similar to rosiglitazone, the long-term safety and adverse effects of pioglitazone have not been well established. In addition, weight gain and edema are typical obvious side effects of pioglitazone, which in turn aggravates heart failure. So the clinical usage of this drug is still under strict supervision in many countries.^[73] Another important insulin sensitizer used in NAFLD therapy is metformin, which showed anti-diabetic effects through increasing fatty acid/glucose metabolism and improving insulin signaling in the liver and adipose tissue.^{[74, 75]} At the molecular level, metformin activates the LKB1/AMPK pathway to accelerate glucose uptake through dissociation of the gluconeogenic CREB-CBP-TORC2 transcriptional complex^[76] and to increase lipolysis by decreasing the expressions of key lipid regulating members (e.g. acetyl-CoA carboxylase, HMG-CoA reductase and fatty acid synthase).^[77] Over the past decades, a large number of clinical trials had been conducted to measure the beneficial effects of metformin in NAFLD, in which the liver function, steatosis and insulin sensitivity improved.^[78-84] Furthermore, metformin therapy exhibited protective effects on metabolic abnormalities and cardiovascular risk, making it a good choice for clinical treatment of NAFLD.^{[85, 86]} However, a recent meta-analysis study found that metformin, when treated with different doses and durations, did not show improvement on liver histology.^[87] In addition, newly published guidelines argue that metformin has no significant effect on liver histology and is not recommended as a specific treatment for liver disease in adults with NASH.^[88] Another promising therapeutic target is the incretin pathway. During NAFLD progression, incretin hormones (e.g. glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1) were dysregulated through the action of dipeptidyl peptidase-4. Therefore, inhibition of dipeptidyl peptidase-4 has been shown to improve insulin resistance, steatosis and inflammation. It also contributes to the improvement of type 2 diabetes clinically.^{[89, 90]}

 

Statins are inhibitors of HMG-CoA reductase in the liver. They are used to reduce the level of cholesterol which is closely associated with the development of atherosclerosis and the incidence of cardiovascular disease.^[91] Regarding the anti-inflammatory and anti-fibrogenic properties of statins, they are also employed in the clinical test for NAFLD prevention and treatment in recent years.^[92] The Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) 3-year prospective investigation found that statins successfully normalized liver enzymes and improved liver function in NAFLD patients. There was a 68% relative risk reduction of cardiovascular events in patients with suspected NAFLD who received statins compared with patients with suspected NAFLD who did not receive statin. Interestingly, among all patients who received statins, patients with suspected NAFLD derived significantly greater benefit from statins compared with those who had no biochemical evidence of NAFLD.^{[11, 93]} Clinical prescription of statins on NAFLD patients significantly attenuated hepatic steatosis and fibrosis in a follow-up study.^[94] Combination of atorvastatin and vitamin C/E also improved the clinical outcome of NAFLD.^[95] However, in another two pilot studies using members of statin class: atorvastatin and simvastatin, exhibited no or controversial statistically important improvement of steatosis, serum aminotransferases, and fibrosis in NAFLD patients.^{[96, 97]} Currently it is not clear if different members of statins possess different effects on NAFLD progression, due to their distinct lipophilicity.^{[98, 99]} Although administration of statins often increases liver enzymes (ALT and AST) and induces acute liver injury in a very small number of patients, the statins therapy is now proven safe.^{[100, 101]} Theoretical data have been collected to support the usefulness of statins in NAFLD treatment even without dyslipidemia, but further prospective studies are needed to verify this finding.^[92] An animal study evaluating the effects of rosuvastatin treatment on high-fat diet induced mouse NAFLD found that insulin resistance, hepatic steatosis, and increased circulating levels of cholesterol were improved by rosuvastatin.^[102]

 

The role of renin-angiotensin system (RAS) in NAFLD development has been extensively investigated, making blockers for angiotensin receptors to be a potential therapeutic strategy of NAFLD.^[103] Telmisartan and losartan, the most common angiotensin II receptor type 1 (AT1) blockers, have been tested if they can ameliorate NAFLD symptoms clinically. In a randomized controlled trial, administration of telmisartan in hypertensive NAFLD patients improved hepatic steatosis, fibrosis, inflammation, and dysregulated lipid metabolism.^[104] A study^[105] in NASH mice further confirmed the finding and suggested additional roles of hepatic macrophage infiltration. In another clinical trial using combined losartan and simvastatin in hypertensive NAFLD patients, hepatic steatosis, visceral adiposity, and HOMA-IR were significantly improved when compared with amlodipine plus simvastatin group.^[106] In a more recent animal study, combination treatment of losartan and new oral iron chelator (deferasirox) exhibited strong suppressive effects on oxidative stress, neovascularization, and hepatic stellate cells activation in NASH rats.^[107]

 

Ursodeoxycholic acid (UDCA) is a bile acid with anti-apoptotic and cytoprotective properties. Thus, it is used as a hepatoprotectant in NAFLD treatment. A 2-year placebo-controlled trial in NAFLD patients found that there was no significant difference between UDCA-treated NAFLD and NAFLD patients, in terms of NAFLD symptoms.^[108] Other studies^{[109, 110]} found that no significant difference was observed regarding mortality or improvement in liver function tests after treatment with normal or high dose of UDCA. Similar to metformin, UDCA is not recommended for the treatment of NAFLD or NASH recently.^[88] Pentoxifylline is another hepatoprotectant with anti-tumor necrosis factor effect and has been used in NAFLD treatment. A 12-month pilot study with pentoxifylline treatment obtained biochemical improvements. However, the side effect (e.g. nausea) is quite noticeable.^[111] A more recent randomized placebo-controlled trial confirmed the beneficial properties of pentoxifylline in reducing steatosis and fibrosis after one year administration in NAFLD patients.^[112]

 

L-carnitine is the precursor of carnitine-palmitoyl-transferase. As a popular food supplement, L-carnitine is used to control body weight because it is involved in the fatty acid transportation in the mitochondria during the breakdown of lipids for the energy production. When introduced to NAFLD patients, L-carnitine improved hepatic steatosis, lipid metabolism, fibrosis, and inflammation.^[113] However, another study^[114] demonstrated that when the same dose and treatment duration of L-carnitine was applied, it failed to exhibit a significant effect on liver histology.

 

Since apoptosis is positively correlated with the severity of NAFLD, reduction of apoptosis provides another possible way to retard this disease. In a randomized, placebo-controlled trial, patients with diagnosed NAFLD received treatment of caspase inhibitor GS-9450 for 4 weeks. When compared with placebo-control, GS-9450 treatment improved ALT levels, but not other metabolic variables.^[115]

 

 

Life style modifications (including weight reduction, dietary modification, and physical exercise) and pharmaceutical treatments (including dietary supplementation) are still two major directions for the therapeutic development of NAFLD in future. The advantages and disadvantages of main current NAFLD therapies are summarized in Table. Generally, for the intervention of lifestyle, numerous clinical reports have extensively investigated the beneficial effects of weight loss, dietary constraints and exercise on NAFLD symptoms but few studies have shown the molecular mechanisms that mediated these effects. For herbal supplementation, several recent studies revealed the protective molecular pathways both in vivo and in vitro, but the possible application of these derivatives in humans still faces some problems, including the control of adverse effects.^[116] In addition, increasing attention is being given to the control of metabolic syndrome risk factors (e.g. obesity, insulin resistance, hyperlipidemia, hypertension, and inflammation), which are proven to induce NAFLD directly or indirectly. Metabolic syndrome itself is also a risk factor of NAFLD and vice versa.^[117] Thus, therapies that effectively ameliorate metabolic syndrome should also possess positive effects on NAFLD treatment. Similar to NAFLD, lifestyle modification is the first and most effective treatment for metabolic syndrome. However, in the majority of cases, pharmaceutical approach is also needed. How to improve symptoms of NAFLD as well as metabolic disorders is another emerging clinical challenge facing us. Regarding the importance of the progression from simple steatosis to NASH, applying suitable pharmacological methods to stop the occurrence of inflammation (e.g. anti-inflammation drugs) is vital for the control of end-stage NAFLD. In recent years, emerging evidence shows a close relationship between gut microbiota and the liver. Homeostasis between bacteria- and host-derived signals in the gut is essential for the maintenance of intestinal barrier function and liver health. Dysregulated gut flora (e.g. small intestinal bacterial overgrowth) is found in a large number of patients with chronic liver diseases and inflammation.^[114] Therefore, therapies targeting disrupted gut-liver axis may also contribute to the retardation of NAFLD (especially NASH) clinically. Another potential therapeutic target is fructose. Recent findings point out that high level of fructose in human diet may induce NAFLD through several mechanisms, including the induction of the metabolic syndrome, copper deficiency, bacterial translocation from the gut to the liver, the formation of advanced glycation end-products and a direct dysmetabolic effect on liver enzymes. Thus, reduction of the intake of fructose-rich foods and beverages may help the control of NAFLD progression.^[118]

 

Although NAFLD is a leading cause of chronic liver disease all over the world, we cannot ignore the individual variability and the need for personalization of NAFLD health care. Recent family and inter-ethnic studies suggest that genetic/family factors may be important risk determinants for NAFLD progression. Genetic polymorphism (e.g. lipid metabolism gene pnpla3) is closely related to the occurrence of steatosis, fibrosis and inflammation in the liver. Daly et al^[119] carefully reviewed genetic polymorphisms that influence the pathological events of NAFLD recently. Therefore, a complete genetic screen before the diagnosis and therapy of NAFLD in clinics seems to be necessary. In addition, several co-factors such as alcohol consumption and cigarette smoke exposure may also significantly affect the incidence and severity of NAFLD. Several studies pointed out that for NAFLD patients, light to moderate alcohol consumption may have hepatic benefits in people with or at risk for NAFLD. However, a recent review by Liangpunsakul and Chalasani^[120] clearly argued that due to the limitations of these studies (e.g. they are largely cross-sectional and used surrogate end points), people with NAFLD should avoid alcohol of any type or amount. So to elucidate the impact of alcohol intake on NAFLD progression is another challenging task for both hepatologists and surgeons. Unlike alcohol consumption, smoking exposure is clearly considered harmful to people with NAFLD. Yuan et al^[121] reported that in mice and cultured hepatocytes, exposure to side-stream whole smoke stimulates lipid accumulation in the liver by modulating AMPK/SREBP-1c pathway. Another large multicohort study^[122] found that smoking history is associated with advanced liver fibrosis in NAFLD patients partly through its influence on insulin resistance. Thus, reducing the exposure to cigarette smoke, whether "first-hand" or "second-hand", is very important for the control and cure of NAFLD.

 

 

During the past decades, therapies against NAFLD received many achievements, in both lifestyle and pharmaceutical interventions. However, we are still far from achieving great therapeutic success in managing NAFLD in clinical studies. To date, pharmaceutical therapies for NAFLD exhibited few positive outcomes in clinical trials, although animal and cellular studies found several promising advancements. Lifestyle interventions are still the most effective methods for control and reversal of NAFLD patients. It is clear that other than body weight reduction, exercise itself is an independent factor for the alleviation of steatosis. Therefore, in clinical setting, when counseling patients on lifestyle changes, regular and moderate intensity exercise should be emphasized. Future studies of pharmaceutical treatment or supplementation are needed to further enhance the therapeutic effects of exercise and other lifestyle modifications. Future advancement of NAFLD therapy should focus on the mechanistic studies on cell based and animal models and human clinical trials of exercise, as well as the combination of lifestyle intervention and pharmaceutical therapy specifically targeting main signaling pathways related to lipid metabolism, oxidative stress and inflammation.

  

 

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