Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common health problem with a high mortality burden due to its liver- and vascular-specific complications. It is associated with obesity, high-fat diet as well as with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). Impaired hepatic fatty acid (FA) turnover together with insulin resistance are key players in NAFLD pathogenesis. Peroxisome proliferator-activated receptors (PPARs) are involved in lipid and glucose metabolic pathways. The novel concept is that the activation of the PPARα subunit may protect from liver steatosis. Fenofibrate, by activating PPARα, effectively improves the atherogenic lipid profile associated with T2DM and MetS. Experimental evidence suggested various protective effects of the drug against liver steatosis. Namely, fenofibrate-related PPARα activation may enhance the expression of genes promoting hepatic FA β-oxidation. Furthermore, fenofibrate reduces hepatic insulin resistance. It also inhibits the expression of inflammatory mediators involved in non-alcoholic steatohepatitis pathogenesis. These include tumor necrosis factor-α, intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Consequently, fenofibrate can limit hepatic macrophage infiltration. Other liver-protective effects include decreased oxidative stress and improved liver microvasculature function. Experimental studies showed that fenofibrate can limit liver steatosis associated with high-fat diet, T2DM and obesity-related insulin resistance. Few studies showed that these benefits are also relevant even in the clinical setting. However, these have certain limitations. Namely, these were uncontrolled, their sample size was small, fenofibrate was used as a part of multifactorial approach, while histological data were absent. In this context, there is a need for large prospective studies, including proper control groups and full assessment of liver histology.

Keywords: Fenofibrate; Non-alcoholic fatty liver disease; Steatohepatitis; Peroxisome proliferator-activated receptors

Core tip: Non-alcoholic fatty liver disease (NAFLD) is a common health problem associated with increased liver- and vascular-specific complications. Dyslipidemia, predominantly hypertriglyceridemia, and insulin resistance play a key role in its pathogenesis. Fenofibrate, by activating peroxisome proliferator-activated receptors appears to decrease liver steatosis in experimental animal studies. This benefit can be attributed to its lipid-lowering potency, together with anti-inflammatory and anti-oxidant actions. Also, fenofibrate increases adiponectin levels and the expression of its liver-active receptor. A potential protective role of fenofibrate against NAFLD has also been implied by few small clinical studies. However, this benefit should be further assessed.