Clinical physiology of NAFLD: a critical overview of pathogenesis and treatment

Abstract

The shared physiopathologic derangements linking nonalcoholic fatty liver disease (NAFLD) with the metabolic syndrome (MetS), along with the biological basis of treatment, will be discussed in this review. The role of macrophages in the ‘adipositis’ of the obese individual mirrors that of Kupffer cells in NAFLD. The gut plays a major role in the pathogenesis of NAFLD by contributing to the development of insulin resistance and inflammation. Mitochondrial dysfunction is the cellular basis for impaired energy homeostasis in adipose, muscle and liver tissues. NAFLD is an essential component of the MetS. However, ethnicity, gender, genetic and hormonal influxes – via body fat distribution – modulate the propensity to develop NAFLD, accounting for the finding that few NAFLD patients are seemingly spared from developing the MetS. Future studies should aim at evaluating the role of hypathalamic inflammation in MetS in humans. Furthermore, moderate calorie restriction and weight loss provide prompt metabolic benefit in NAFLD, with indications suggesting that the Mediterranean-type diet has the potential for curing the MetS and NAFLD. The controversial role of alcohol and the molecular mechanism of actions exerted by physical training on NAFLD are discussed in this article. Additionally, specific molecular/cellular targets for innovative treatment strategies based on NAFLD physiology are also reviewed.

Keywords::

• adipose tissue
• alcohol
• diet
• exercise
• fructose
• hypothalamus
• insulin resistance
• metabolic syndrome
• mitochondria
• molecular mechanism
• muscle
• natural history
• nonalcoholic fatty liver disease
• nonalcoholic steatohepatitis
• pathogenesis
• treatment
• Type 2 diabetes

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing assistance was utilized in the production of this manuscript. English editing by Jacqueline Mole is gratefully acknowledged.

Notes

FFA: Free fatty acids; TZD: Thiazolidinedione.

Modified from [156,193,194].