Elsevier

Life Sciences

Volume 92, Issue 2, 7 February 2013, Pages 114-118
Life Sciences

Minireview
Nonalcoholic fatty liver disease: Current and potential therapies

https://doi.org/10.1016/j.lfs.2012.11.004Get rights and content

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury worldwide. It covers a wide spectrum of hepatic disorders ranging from simple steatosis, through steatohepatitis (steatosis with inflammation), to cirrhosis. The molecular and cellular mechanisms underlying hepatic injury in NAFLD are not clear. Several evidences suggest that multiple mechanisms including insulin resistance, oxidative stress, inflammation, and genetic factors interact to initiate the development of NAFLD. Despite that there is currently no approved drug therapy for NAFLD, many approaches appear to be beneficial. Insulin sensitizers, antioxidants and antiinflammatory agents showed promising effects. This review highlights the current as well as the potential therapies of NAFLD.

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.

  1. Download : Download high-res image (161KB)
  2. Download : Download full-size image

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)

  • A.J. Sanyal et al.

    Non-alcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities

    Gastroenterology

    (2001)
  • A. Tailleux et al.

    Roles of PPARs in NAFLD: potential therapeutic targets

    Biochim Biophys Acta

    (2012)
  • D.M. Torres et al.

    Diagnosis and therapy of nonalcoholic steatohepatitis

    Gastroenterology

    (2008)
  • L. Valenti et al.

    Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease

    Gastroenterology

    (2002)
  • L.B. Van Wagner et al.

    Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial

    Ann Hepatol

    (2011)
  • E.L. Yu et al.

    Non-alcoholic fatty liver disease: epidemiology, pathophysiology, diagnosis and treatment

    Paediatr Child Health

    (2010)
  • Q.M. Anstee et al.

    Mouse models in non-alcoholic fatty liver disease and steatohepatitis research

    Int J Exp Pathol

    (2006)
  • E. Bugianesi et al.

    Relative contribution of iron burden, HFE mutations and insulin resistance to fibrosis in nonalcoholic fatty liver

    Hepatology

    (2004)
  • R.E. Castro et al.

    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

    (2012)
  • D. Dey et al.

    Inhibition of insulin receptor gene expression and insulin signaling by fatty acid: interplay of PKC isoforms therein

    Cell Physiol Biochem

    (2005)
  • H. Dong et al.

    Chinese herbal medicine in the treatment of nonalcoholic fatty liver disease

    Chin J Integr Med

    (2012)
  • Cited by (72)

    • Non-alcoholic fatty liver disease and thrombocytopenia IV: its association with granulocytopenia

      2022, Hematology, Transfusion and Cell Therapy
      Citation Excerpt :

      Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury worldwide1; it encompasses a wide spectrum of liver disorders ranging from steatosis, through steatohepatitis and overt liver cirrhosis.

    • Gut inflammation exacerbates hepatic injury in the high-fat diet induced NAFLD mouse: Attention to the gut-vascular barrier dysfunction

      2018, Life Sciences
      Citation Excerpt :

      These data indicated that there exists disruption of GVB in NASH and disruption of GVB aggravated liver inflammation and fibrosis in a diet-induced NAFLD model, suggesting a role of disruption of GVB in inflammatory transport and the progression of NAFLD to NASH. NAFLD is a typical manifestation of metabolic syndrome, which may be the result of multiple hits, not only the primary metabolic disorder with fatty degeneration and lipid accumulation induced by insulin resistance [20,21]. The hits originate from intestinal dysfunction should be crucial issues and highly concerned, due to the closely anatomical and functional relations of the gut-liver axis [5,7,12,22].

    View all citing articles on Scopus
    View full text