MinireviewNonalcoholic fatty liver disease: Current and potential therapies
Graphical abstract
NAFLD: non alcoholic fatty liver disease. The circle represents the interacting pathological mechanisms involved in development of NAFLD. The rectangles represent the promising drug therapies.N.B.: Currently, there is no approved medical or surgical treatment for NAFLD.
Introduction
Nonalcoholic fatty liver disease (NAFLD), first described in 1981, is a term that represents a spectrum of hepatic disorders ranging from simple triglyceride (TG) accumulation in hepatocytes (hepatic steatosis) through hepatic steatosis with inflammation (steatohepatitis) commonly known as nonalcoholic steatohepatitis (NASH), to cirrhosis (Farrell and Larter, 2006). By definition, NAFLD is seen in people whose daily alcohol intake is less than 10 g for women and less than 20 g for men. NAFLD affects 10–24% of the general population in various countries. The prevalence of NAFLD rises to 57.5–74% in obese persons. It affects 2.6% of children, and 22.5–58.5% of obese children (Tarantino et al., 2007). In NAFLD cirrhosis, 30% to 40% of patients will experience a liver-related death (McCullough, 2006). Currently, there is no satisfying therapeutic strategy for NAFLD. This review highlights the available as well as the potential therapies of NAFLD.
Section snippets
Molecular mediators of NAFLD
Understanding the pathophysiology of NAFLD is extremely important to develop sound therapeutic interventions. Despite the exact pathology underlying NAFLD is unknown, there is an accepted concept for the pathophysiology of NAFLD that is called “multiple hit” hypothesis (McCullough, 2006). According to this hypothesis, multiple factors interact for the development of NAFLD (Fig. 1). The first hit is the accumulation of fat in hepatocytes mostly due to insulin resistance (IR) (Chitturi et al.,
Insulin resistance
Insulin resistance (IR) is defined as decreased insulin mediated uptake of glucose in tissues such as skeletal muscle and adipocytes. The degree of IR has been correlated with the severity of NAFLD (Bugianesi et al., 2004). Peripheral IR leads to an influx of free fatty acids (FFAs) to the liver both by decreased suppression of lipolysis and increased de novo lipogenesis in the liver. The subsequent accumulation of fat within the hepatocytes leads to the development of hepatic IR (Kim et al.,
Oxidative stress/mitochondrial dysfunction
Oxidative stress occurs as a result of either excess generation of reactive oxygen species (ROS) within the hepatocyte or reduced antioxidant defences. In the liver, oxidative stress results in activation of hepatic stellate cells as well as accumulation of fat within hepatocytes. Oxidative stress not only results in the generation of ROS, but also enhances peroxisomal and mitochondrial β-oxidation. Peroxisomal β-oxidation results in the generation of acyl-coenzyme A, which if left
Inflammation/adipocytokines
Adipose tissue secretes a number of physiologically active peptides. These peptides or “adipocytokines” can be classified as proinflammatory, such as leptin, TNF-α and interleukin-6 (IL-6), or antiinflammatory and anti-steatotic, such as adiponectin. They all have a role in the regulation of adipocyte metabolism, with a direct role in several insulin-mediated processes (McAvoy et al., 2006). A role of TNF-α in the link between adipose tissue mass and IR has been reported (Lofgren et al., 2000).
Immune response
Alterations in immune response have been implicated in the pathogenesis of NAFLD. NAFLD is associated with increased levels of the proinflammatory T helper 1-associated cytokines TNF-α and interleukin-12 (IL-12). In NAFLD loss or depletion of hepatic natural killer T (NKT) cells was reported. NKT cells and Kupffer cell-derived IL-12 may have a regulatory role during pathogenesis of NAFLD (Kremer et al., 2010).
Genetic factors
Valenti et al. examined TNF-α polymorphisms and concluded that these may also represent a susceptibility genotype for IR and NAFLD. It is however regarded that IR in patients with NAFLD is a result of multiple gene polymorphisms interacting with environmental factors. Genetic factors are thought to be more important in NAFLD patients with a normal body mass index (BMI) (Valenti et al., 2002).
Adiponutrin/patatin-like phospholipase domain-containing 3 gene (PNPLA3) was the first identified genome
Diagnosis of NAFLD
There are no routine boimarkers for NAFLD. Currently, liver biopsy is the gold standard for diagnosis of NAFLD but there is a growing consensus that NAFLD can be diagnosed without liver biopsy, using combinations of clinical history, laboratory tests (e.g. liver function tests) and ultrasound. Transient elastography, computerized tomography scanning and magnetic resonance spectroscopy may be used (Shyangdan et al., 2011).
Current treatment options
Currently, there is no approved treatment (medical or surgical) for NAFLD. There is no available prospective evidence showing the outcome of any treatment on long-term outcomes, such as the development of cirrhosis or hepatocellular carcinoma (Shyangdan et al., 2011).
Recently, treatment for NAFLD has been systematically reviewed by Musso et al. (2010) as well as by Shyangdan et al. (2011) and both concluded that body weight loss is the only proven effective therapy for NAFLD. However, many
Insulin sensitizers
Insulin sensitizing agents are the most promising drugs in NAFLD management; there is evidence that both biguanides (e.g. metformin) and glitazones (e.g. pioglitazone and rosiglitazone) produce positive effects on biochemical parameters with variable effects on liver histology. Metformin acts through the activation of adenosine monophosphate-activated protein kinase, a master regulator of glucose and lipid metabolism. Glitazones decrease insulin resistance via activation of PPAR-γ causing
Conclusion
Development of NAFLD is due to multiple interrelated factors mainly insulin resistance, oxidative stress, inflammation and genetic predisposition. Consequently, the potential therapies for NAFLD target one or more of these factors.
Conflict of interest statement
There are no conflicts of interest.
Acknowledgment
The authors wish to thank Professor Dr. Aly Abdelrahman, professor and chairman of pharmacology department, faculty of medicine, Minia University, Egypt, for critical reading of the manuscript.
References (43)
- et al.
Modulation of sterol regulatory element binding proteins (SREBPs) as potential treatments for nonalcoholic fatty liver disease (NAFLD)
Drug Discov Today
(2007) - et al.
Adiponectin: is it a novel treatment modality to alleviate liver injury in non-alcoholic fatty liver disease (NAFLD)?
Med Hypotheses
(2008) - et al.
Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity?
J Hepatol
(2002) - et al.
Probiotics reduce inflammatory response induced by high fat diet in liver of young rat: new insights for NAFLD treatment
J Nutr
(2009) - et al.
Nitro-aspirin is a potential therapy for non alcoholic fatty liver disease
Eur J Pharmacol
(2011) - et al.
Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors
Gastroenterology
(2009) - et al.
NAFLD treatment: cognitive-behavioral therapy has entered the arena
J Hepatol
(2005) - et al.
Alpha-lipoic acid attenuates methionine choline deficient diet-induced steatohepatitis in C57BL/6 mice
Life Sci
(2012) - et al.
Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet
Eur J Pharmacol
(2006) - et al.
Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease
J Biol Chem
(2004)
Non-alcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities
Gastroenterology
Roles of PPARs in NAFLD: potential therapeutic targets
Biochim Biophys Acta
Diagnosis and therapy of nonalcoholic steatohepatitis
Gastroenterology
Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease
Gastroenterology
Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial
Ann Hepatol
Non-alcoholic fatty liver disease: epidemiology, pathophysiology, diagnosis and treatment
Paediatr Child Health
Mouse models in non-alcoholic fatty liver disease and steatohepatitis research
Int J Exp Pathol
Relative contribution of iron burden, HFE mutations and insulin resistance to fibrosis in nonalcoholic fatty liver
Hepatology
miR-34a/SIRT1/p53 is suppressed by ursodeoxycholic acid in rat liver and activated by disease severity in human non-alcoholic fatty liver disease
J Hepatol
Inhibition of insulin receptor gene expression and insulin signaling by fatty acid: interplay of PKC isoforms therein
Cell Physiol Biochem
Chinese herbal medicine in the treatment of nonalcoholic fatty liver disease
Chin J Integr Med
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