Chemokine ligand 2 and paraoxonase-1 in non-alcoholic fatty liver disease: The search for alternative causative factors

Abstract

The incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) is constantly increasing. Despite this is apparently associated with the growing increase in obesity, insulin resistance and obesity-related metabolic disturbances their presence is not a necessary or sufficient condition to explain the accumulation of fat in the liver. Conversely, NAFLD is a predictor of other metabolic risks. NAFLD is currently the most frequent chronic liver disease but should not be considered benign or anecdotic because a considerable proportion of patients with NAFLD progress to cirrhosis and end-stage liver disease. Consequently, the search for alternative molecular mechanisms with therapeutic implications in NAFLD and associated disorders deserves a careful consideration. Mitochondria are possible targets as these organelles generate energy from nutrient oxidation. Some findings, generated in patients with extreme obesity and in murine models, support the notion that NAFLD could be a mitochondrial disease. This is plausible because mitochondrial dysfunction affects the accumulation of lipids in hepatocytes and promotes lipid peroxidation, the production of reactive oxygen species, the release of cytokines causing inflammation and cell death. Here we discuss basic research and mechanistic studies targeting the role of chemokine ligand 2 in liver inflammation and that of the paraoxonases in the oxidative stress. Their combination and association with mitochondrial dysfunction may uncover mechanisms underlying the progression of NAFLD and may help to identify novel therapeutic targets.

Keywords: Biomarkers; Cytokines; Inflammation; Metabolism; Mitochondrial dysfunction; Metabolic profiling; Obesity; Oxidation; Risk factors

Core tip: Recently acquired knowledge on the role of oxidation, inflammation and mitochondrial dysfunction in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) suggests a crucial role in the search for biological markers and therapeutic targets to alleviate the progression of the disease. Classically associated with obesity, the pathogenesis of NAFLD is extremely complex and mostly unknown. Consequently, the correct clinical management and prevention has not been established yet. Despite disparate results in the literature, mainly due to the different methods to measure the oxidative stress, there is currently no doubt that oxidative stress plays a crucial role. Similarly, the infiltration of monocytes, mainly due to the action of chemokines, is a relevant factor. However, to uncover the actual molecular mechanisms has proven to be more difficult than expected. The role of both oxidation and inflammation could be considered defensive and/or causative but the combination of these and other mechanisms may improve the understanding of NAFLD as a manifestation of mitochondrial disease. J. Camps and J. Joven. Chemokine ligand 2 and paraoxonase-1 in non-alcoholic fatty liver disease: the search for alternative causative factors.