Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications

Abstract

Pathological increases in cell death in the liver as well as in peripheral tissues has emerged as an important mechanism involved in the development and progression of nonalcoholic fatty liver disease (NAFLD). An increase in hepatocyte cell death by apoptosis is typically present in patients with NAFLD and in experimental models of steatohepatitis, while an increase in adipocyte cell death in visceral adipose tissue may be an important mechanism triggering insulin resistance and hepatic steatosis. The two fundamental pathways of apoptosis, the extrinsic (death receptor-mediated) and intrinsic (organelle-initiated) pathways, are both involved. This article summarizes the current knowledge related to the distinct molecular and biochemical pathways of cell death involved in NAFLD pathogenesis. In particular, it will highlight the efforts for the development of both novel diagnostic and therapeutic strategies based on this knowledge.

Figure 1

Hematoxylin and eosin-stained liver tissue showing apoptotic hepatocytes (arrow) in a patient with nonalcoholic steatohepatitis (magnification ×200).

Figure 2. Apoptotic pathways in nonalcoholic fatty liver disease

Apoptosis occurs via two molecular pathways, extrinsic and intrinsic. The extrinsic pathway involves death ligand-induced activation of receptors, resulting in the formation of the death complex. The intrinsic pathway is activated by cellular stress and mitochondrial dysfunction. ER stress can induce apoptosis through JNK and CHOP, which activate the proapoptotic protein Bax, leading to mitochondrial dysfunction. Both apoptotic pathways activate intracellular proteases, the caspases, that cleave cell components in an organized way. The engulfment of the resulting apoptotic bodies by Kupffer cells promotes hepatic fibrosis and inflammation through the activation of stellate cells and the release of cytokines. CHOP: C/EBP homologous protein; Cyto c: Cytochrome c; ER: Endoplasmic reticulum; FasL: Fas ligand; PERK: PKR-like ER kinase; TRAIL: TNF-related apoptosis-inducing ligand.

Figure 3. Cytokeratin 18 and soluble Fas levels as noninvasive markers for nonalcoholic steatohepatitis

Caspase 3-generated CK18 fragments are produced during hepatocyte apoptosis and can be detected using a monoclonal antibody (M30), both in the liver and in blood. The Fas–Fas ligand complex is a key part of the extrinsic pathway in the hepatocyte apoptotic cascade, and soluble Fas can be measured in the serum using ELISA. CK18: Cytokeratin 18.