Peroxisome Proliferator-Activated Receptor α Activation Induces Hepatic Steatosis, Suggesting an Adverse Effect

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic triglyceride accumulation, ranging from steatosis to steatohepatitis and cirrhosis. NAFLD is a risk factor for cardiovascular diseases and is associated with metabolic syndrome. Antihyperlipidemic drugs are recommended as part of the treatment for NAFLD patients. Although fibrates activate peroxisome proliferator-activated receptor α (PPARα), leading to the reduction of serum triglyceride levels, the effects of these drugs on NAFLD remain controversial. Clinical studies have reported that PPARα activation does not improve hepatic steatosis. In the present study, we focused on exploring the effect and mechanism of PPARα activation on hepatic triglyceride accumulation and hepatic steatosis. Male C57BL/6J mice, Pparα-null mice and HepG2 cells were treated with fenofibrate, one of the most commonly used fibrate drugs. Both low and high doses of fenofibrate were administered. Hepatic steatosis was detected through oil red O staining and electron microscopy. Notably, in fenofibrate-treated mice, the serum triglyceride levels were reduced and the hepatic triglyceride content was increased in a dose-dependent manner. Oil red O staining of liver sections demonstrated that fenofibrate-fed mice accumulated abundant neutral lipids. Fenofibrate also increased the intracellular triglyceride content in HepG2 cells. The expression of sterol regulatory element-binding protein 1c (SREBP-1c) and the key genes associated with lipogenesis were increased in fenofibrate-treated mouse livers and HepG2 cells in a dose-dependent manner. However, the effect was strongly impaired in Pparα-null mice treated with fenofibrate. Fenofibrate treatment induced mature SREBP-1c expression via the direct binding of PPARα to the DR1 motif of the SREBP-1c gene. Taken together, these findings indicate the molecular mechanism by which PPARα activation increases liver triglyceride accumulation and suggest an adverse effect of fibrates on the pathogenesis of hepatic steatosis.

Effect of oleoylethanolamide on diet-induced nonalcoholic fatty liver in rats

“…Stimulated de novo lipogenesis has been observed after treatment with PPAR-a agonists in many experiments (24,25). In the 6-week short-term drug administration experiment, we did observe that fenofibrate significantly up-regulates the expression level of SCD-1 and SREBP-1c mRNA in the rat liver as the previous studies have been shown.…”

Fenofibrate Treatment Attenuated Chronic Endoplasmic Reticulum Stress in the Liver of Nonalcoholic Fatty Liver Disease Mice

“…This inconsistency with our study could be related to the shorter feeding time of only 2 weeks of the high-fructose diet and fenofibrate administration [10]. Another report found that hepatic steatosis was induced after male C57BL/6J mice were directly administered with fenofibrate through daily gavage for 10 days.…”

“…Fenofibrate, a specific agonist of PPARα, represents the most frequently used clinical drug for decreasing hypertriglyceridemia and obesity. Several experimental observations indicate that activation of PPARα could prevent hepatic triglyceride (TG) accumulation and could have a therapeutic effect against NAFLD [6], but the precise mechanism of this drug in ER stress has not yet been fully elucidated in the NAFLD liver [7,8], and there has even been some inconsistency [9,10]. Therefore, it is necessary to study whether fenofibrate treatment influences ER stress and which pathway it uses in the NAFLD liver.…”

Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction

“…As signs of incomplete oxidation are exacerbated by fenofibrate, long term treatment could be ineffective, or even aggravate hepatic metabolic dysfunction, as was also proposed [52].…”

“…Fibrates have been proposed in the treatment of NAFLD but some authors found a negative outcome [52]. As signs of incomplete oxidation are exacerbated by fenofibrate, long term treatment could be ineffective, or even aggravate hepatic metabolic dysfunction, as was also proposed [52].…”