br Introduction Nonalcoholic fatty liver disease NAFLD is a

Introduction Nonalcoholic fatty liver disease (NAFLD) is a clinicopathologic spectrum of liver pathologies associated with excessive accumulation of fat in the liver. This spectrum is continuous but can be graded based on pathological features; in increasing severity, these are: bland steatosis, steatohepatitis, fibrosis and cirrhosis. NAFLD affects 31% of the US population, and is strongly correlated with the high incidence of obesity in Western cultures (Browning et al). Simple hepatic steatosis or non-alcoholic fatty liver (NAFL) is a largely benign and reversible condition defined by an excess accumulation of lipid droplets in the liver. However, when non-alcoholic hepatic fat accumulation is associated with a significant inflammatory reaction—seen as lobular inflammation and cellular ballooning injury on histopathology—the pathology is considered nonalcoholic steatohepatitis (NASH). An estimated 20–33% of individuals with NAFL patients show evidence of NASH on histopathology. Further progression of the disease in the setting of ongoing inflammation results in fibrosis and eventually occurs in 20% of individuals with NASH. Individuals with NASH progress to fibrosis and cirrhosis at a rate of 7–10% annually. Annual incidence of hepatocellular cancer and liver related death in patients with NASH related cirrhosis is around 2.6% and 1.4–3% respectively. The prevalence of NAFL reaches up to 90% in the obese population, and more than half of these show evidence of NASH based on histopathology. Furthermore, NAFLD is commonly associated with features of type 2 diabetes and metabolic syndrome. For instance, among individuals with type 2 ezh2 inhibitor receptor (T2D) up to 70% have NAFL, and NASH is evident in ~67% of those biopsied. Reciprocally, T2D is seen in 30% of patients with NAFLD. This strong association of NAFLD with metabolic syndrome, suggests that mechanisms may be shared between these pathologies, in particular the conditions of maladaptive inflammation and insulin resistance observed in both. One biochemical pathway that is likely to be relevant but has not yet been extensively studied in NAFLD, is the eicosanoid generating lipoxygenases pathway. In this review, we summarize the current understanding of the pathogenesis of NAFLD, introduce the pertinent mechanisms by which 12-LOX could play a part in NAFLD pathogenesis, and discuss current and potential new therapeutic approaches.
NAFLD pathogenesis NAFLD is a complex disease, and accordingly its etiology involves multiple interacting factors, such as nutrient excess, obesity and metabolic syndrome. In such “overfed” states, free fatty acids (FFAs) are directed to adipose tissue where they are converted into triglycerides under the control of the insulin signaling pathway. However, with chronic over-nutrition and obesity the presence of low grade inflammation in adipose tissues drives the development of peripheral insulin resistance, creating a state of relative insulin deficiency. Under these conditions, lipolysis is no longer inhibited in adipocytes by insulin, leading to an increase in circulating FFAs; these FFAs in turn are sequestered by the liver for lipogenesis. Furthermore, in states of insulin resistance gluconeogenesis is uninhibited, while enhancing de novo lipogenesis. This is referred to as selective insulin resistance, as in normal conditions insulin inhibits gluconeogenesis while promoting de novo lipogenesis (Fig. 1). Moreover, locally generated lipid products from cells in the liver (hepatocytes, invading immune cells) may also contribute substrate for lipogenesis. Together, the abovementioned dysfunctions drive the accumulation of triglycerides as lipid droplets in the liver, which upon exceeding 5% of the hepatocytes on histopathology is clinically defined as nonalcoholic fatty liver (NAFL), or bland steatosis. A considerable percentage of these patients (20–30%) develop hepatic inflammation and progress to nonalcoholic steatohepatitis (NASH). Although the transition from NAFL to NASH generally occurs in the setting of obesity and insulin resistance, the triggering events and downstream mechanism of progression are not yet completely understood; however it is likely that progression requires two hits that lead to the disruption of distinct molecular pathways. Traditionally it has been hypothesized that a first hit results in development of simple steatosis, while a second hit results in progression from simple steatosis to steatohepatitis. In recent years, a consensus has been emerging that the first of these hits encompasses insulin resistance, continued nutrient excess, and impaired autophagy that lead to steatosis, and that the second of these hits encompasses oxidative stress, ER stress, impaired autophagy, altered intestinal microbiome and intestinal translocation that allow progression to steatohepatitis. The hepatocyte alone is not responsible for the spectrum of molecular disorders leading to steatohepatitis, and other cells such as adipocytes and hepatic dendritic cells, NK-T cells, CD4 and CD8 T cells likely contribute. In the rest of this section, we review three interconnected molecular pathways in hepatocytes—autophagy, ER stress and oxidative stress—that have been implicated in NAFLD progression and introduce 12-LOX pathway which we believe plays an important role in the pathogenesis of NAFLD. Fig. 1 provides an overview of the pathogenesis of NAFLD described in this paper.