Exploring lipid-related treatment options for the treatment of NASH.

Abstract

The liver plays a major role in lipid metabolism, importing free fatty acids (FFA) and manufacturing, storing and exporting lipids: derangements in any of these processes can lead to non-alcoholic fatty liver disease (NAFLD) [1]. NAFLD can be seen as the result of an imbalance between lipid availability and lipid disposal resulting in hepatic steatosis [2]. NAFLD is considered by many as the hepatic manifestation of insulin resistance (IR) and is strongly associated with the metabolic syndrome [3]. The rapid increase in obesity and diabetes mellitus (DM) during the last decade is associated with an increase in the prevalence of NAFLD, making it the most common cause of chronic liver disease in the Western countries with up to 30% of the population affected [4]. Histological evaluation is the gold standard for precisely estimating the degree of liver damage caused by simple steatosis or by non-alcoholic steatohepatitis (NASH). NASH is a disturbance at the end of NAFLD spectrum characterized by hepatocellular injury/inflammation/macrophage infiltration with or without fibrosis [5]. The individuals with NAFLD develop NASH in 10% of the cases, 8-26% progress to cirrhosis and these patients are also at risk of developing hepatocellular carcinoma (HCC) [6]. As recently highlighted by the guidelines of the American Association for the Study of Liver Diseases (AASLD) [7], patients with NAFLD and NASH are at increased risk for cardiovascular disease (CVD) (their most common cause of death) [8]. Therefore, patients with NAFLD and NASH should be stratified for such risk and their CVD factors, including dyslipidemia, should be managed accordingly [9]. At the cellular level, defects in the insulin signaling pathways contribute to the increase of FFA flux in the liver which in turn activates a series of signaling cascades which lead to the phosphorylation of several substrates; in the case of IR there is a decreased insulin receptor kinase activity resulting in lower AKT activity [10]. Insulin is the main driver of the global response to nutrient ingestion, and acts on hepatic fat metabolism through the phosphatidylinositol kinase signaling pathway by accumulating the intracellular lipid small messenger phosphatidylinositol [3,4,5]-trisphosphate. This situation is reproduced faithfully by phosphatase and tensin homologue (PTEN) loss, which similarly accompanies fatty liver development [11-17]. Besides the PTEN/AKT and downstream effectors, de novo fatty acid synthesis is regulated by a plethora of other transcription factors [2]. The mechanisms behind the progression of steatosis to NASH are not completely understood; in particular the factors that lead to increasing hepatocellular damage after triglyceride (TG) accumulation. According to the ‘two-hit’ theory, the ‘first hit’ is an imbalance in hepatic lipid accumulation the likely cause being IR which leads to an increased traffic of FFA in the hepatocytes; then follows the ‘second hit’, represented by inflammatory cytokines/adipokines, mitochondrial dysfunction and oxidative stress, promoting apoptosis through several pathways that lead to inflammatory infiltrates in the liver that may progress to fibrosis [18]. This old model is now revitalized by recent studies analyzing the role of the gut microbiota. The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) family of pattern-recognition molecules NLRP6 and NLRP3 take part to cytosolic protein complexes termed inflammasomes, which in turn have various roles in immune defense [19]. The NLRP6 and NLRP3 inflammasomes and the downstream cytokine interleukin-18 (IL-18) negatively regulate NAFLD/NASH progression, by regulating the activity of the gut microbiota: changed interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing may govern NAFLD progression [20]. Inflammasome sensing has also been proposed as a mechanism in mac