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, fenofibraterelated 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.

Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα

“…Taken together, these results suggest that PPARα or fatty acid oxidation disorders may also participate in the development of human NAFLD. In addition, some studies have demonstrated that PPARα agonist improved liver steatosis in several obese mice models (57)(58)(59). However, the effect of PPARα agonists on improving human NAFLD is still controversial, although some studies have shown positive effects (60,61).…”

Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

“…It seems that insulin-sensitizing action of fenofibrate is more important to counter hepatic steatosis than its lipid-lowering property. A recent study showed a significant decrease in hepatic transaminases coupled with a marked decrease of hepatocellular ballooning in humans [54,55] . As far as mice models of NASH are concerned, APOE2 mice fed a western diet showed decreased hepatic macrophage accumulation, which precedes lipid accumulation within hepatocyte, and expressive reduction of lipotoxicity after treatment with fenofibrate.…”

Type 2 Diabetes and Developmental Origin of Non-Alcohol Fatty Liver Disease and Future Directions of Treatment

“…Fenofibrate was found to deplete hepatic triglycerides accumulation in high fat diet [131], reversed the development of hepatic steatosis, necroinflammation and collagen deposition [132]. The drug activated PPAR-α which enhanced hepatic fatty acid turnover, fatty acid transport protein, fatty acid binding protein, carnitine palmitoyltransferase II, as well as medium-and long-chain acyl-CoA dehydrogenase and acyl-CoA oxidase [133].…”