Pathophysiology of NASH: perspectives for a targeted treatment

Abstract

Non alcoholic steatohepatitis (NASH) is the more severe form of nonalcoholic fatty liver disease. In NASH, fatty liver, hepatic inflammation, hepatocyte injury and fibrogenesis are associated, and this condition may eventually lead to cirrhosis. Current treatment of NASH relies on the reduction of body weight and increase in physical activity, but there is no pharmacologic treatment approved as yet. Emerging data indicate that NASH progression results from parallel events originating from the liver as well as from the adipose tissue, the gut and the gastrointestinal tract. Thus, dysfunction of the adipose tissue through enhanced flow of free fatty acids and release of adipocytokines, and alterations in the gut microbiome generate proinflammatory signals that underlie NASH progression. Additional 'extrahepatic hits' include dietary factors and gastrointestinal hormones. Within the liver, hepatocyte apoptosis, ER stress and oxidative stress are key contributors to hepatocellular injury. In addition, lipotoxic mediators and danger signals activate Kupffer cells which initiate and perpetuate the inflammatory response by releasing inflammatory mediators that contribute to inflammatory cell recruitment and development of fibrosis. Inflammatory and fibrogenic mediators include chemokines, the cannabinoid system, the inflammasome and activation of pattern-recognition receptors. Here we review the major mechanisms leading to appearance and progression of NASH, focusing on both extrahepatic signals and local inflammatory mechanisms, in an effort to identify the most promising molecular targets for the treatment of this condition.

Figure 1. Central role of free fatty acids (FFA) in the pathogenesis of NAFLD

In the presence of insulin resistance, the majority of FFA reaching the liver derive from adipose tissue lipolysis. Lipids from the diet or de novo lipogenesis also contribute to expand the FFA pool. In the hepatocyte, FFA may be oxidized at mitochondrial and extramitochondrial sites, or incorporated in triglycerides. These in turn may be accumulated in lipid droplets, leading to steatosis or secreted in the circulation as VLDL, leading to a proatherogenic lipid pattern.

Figure 2. The fate of excess fatty acids is linked to the severity of nonalcoholic fatty liver disease

Increased hepatic inflow of fatty acids due to peripheral insulin resistance is associated in some patients with lipotoxic injury, while in other to limited damage. Experimental evidence indicates that accumulation of triglycerides may represent a protective mechanism to limit the toxic action of fatty acids and other lipotoxic products. In the presence of lipotoxicity, steatohepatitis develops possibly leading to end stage liver disease and its complications.

Figure 3. Contribution of the adipose tissue to the development of nonalcoholic steatohepatitis

In the lean subject, M2-polarized macrophages and regulatory T cells (Treg) predominate in the vascular stromal fraction. Weight gain leads to expansion of the adipose tissue, resulting in tissue hypoxia and adipocyte apoptosis, leading to secretion of chemotactic cytokines such as CCL2 (MCP-1). CCL2 secretion recruits M1-polarized macrophages that secrete proinflammatory cytokines, contributing to insulin resistance, which increases lipolysis and the delivery of free fatty acids (FFA) to the liver. The expanded and inflamed adipose tissue also causes an imbalance in adipokine secretion, with an increase in leptin and a decrease in adiponectin circulating levels.

Figure 4. Dietary factors influence the development of steatohepatitis

Saturated fatty acids, particularly palmitic acid, are highly lipotoxic and may lead to apoptotic cell death. In contrast, n-3 PUFA have a protective effect on steatosis. Free cholesterol targets the mitochondria, and contributes to lipotoxicity and apoptosis. Fructose favors steatosis and contributes to injury, inflammation and fibrogenesis increasing the availability of lipopolysaccharide (LPS), increasing the levels of advanced glycation end-products (AGE), increasing iron and depleting copper.

Figure 5. Pivotal role of activated Kupffer cells in the pathogenesis of nonalcoholic steatohepatitis and fibrogenesis

Increased levels of lipoipolysaccaride (LPS) and lipotoxic lipid products lead to activation of Kupffer cells, which release chemotactic factors (e.g. CCL2), and proinflammatory cytokines, and generate oxidative stress-related products including reactive oxygen species (ROS). These factors contribute to hepatocyte injury, which in turn, through danger signals, cause further activation of toll-like receptors (TLRs). In addition, inflammation and damage contribute to hepatic stellate cell activation and fibrosis.