Obesity is now considered a worldwide epidemic. In the US, more than 30% of the adult population is currently obese, representing a two-fold increase since 1980 [1,2]. Concomitant with this burgeoning obesity epidemic has been a significant increase in obesity-associated diseases, most notably type 2 diabetes and cardiovascular disease [1,3].
Non-alcoholic fatty liver disease (NAFLD) is a newly emerging obesity-related disorder characterized by fatty infiltration of the liver in the absence of chronic alcohol consumption [4–6]. Similar to obesity, the prevalence of NAFLD has nearly doubled since 1980 [4,6,7]. Data from the most recent National Health and Nutrition Examination Survey (NHANES 1999–2002) suggest that the current prevalence of NAFLD is approximately 8.9% of the US population, as indicated by elevated levels of serum alanine aminotransferase (ALT) . Diagnosis based solely on ALT levels, however, has been shown to underestimate the prevalence of NAFLD when compared to liver biopsies and radiographic techniques (e.g. magnetic resonance spectroscopy and computed tomography) [9,10]. Using these latter techniques, it has been estimated that NAFLD may affect 25–30% of the general population and up to 80% of obese and diabetic individuals . Perhaps most alarming, NAFLD is emerging as a common pediatric disease, afflicting approximately 3–9% of all children in the US and up to 50% of obese children .
Recent data have demonstrated that NAFLD is closely associated with visceral adiposity, dyslipidemia and insulin resistance, and has been described as the hepatic component of the metabolic syndrome . NAFLD ranges from fat accumulation in the liver (steatosis), to steatosis accompanied by inflammation and necrosis with or without fibrosis (non-alcoholic steatohepatitis or NASH), to end-stage liver disease [5,7]. Individuals with NAFLD often remain asymptomatic for decades. This indolent nature of NAFLD has contributed to an under-appreciation of its potential hazards . However, NAFLD is now recognized as the most common cause of chronic liver enzyme elevations and cirrhosis [5,13], and more recent data suggest that the disease is independently associated with the development of cardiovascular disease and overall- and obesity-related mortality .
In light of the increasing prevalence and health consequences of NAFLD, there is a critical need to identify the mechanisms that mediate the development and progression of the disease. Research over the last decade has greatly enhanced our understanding of the disease in this regard, although numerous questions remain unanswered. For example, what metabolic abnormalities initiate the development of NAFLD. Also, what biochemical processes mediate the transition from simple steatosis to NASH. The current review will focus primarily on data from our laboratory and elsewhere examining the potential role of fatty acid composition in the progression of the disease. A putative role for the endoplasmic reticulum (ER) in the development and progression of NAFLD will also be discussed. Finally, we will compare and contrast the role of fatty acid composition in the pathophysiology of NAFLD with that of alcoholic fatty liver disease (AFLD), a disease histologically identical to NAFLD but with some intriguing differences.