title: 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.
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yan
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China; Institute of Pharmacology, Shandong University, Jinan, Shandong, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Cao
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Jing
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Chen
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D011345:Fenofibrate / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D050155:Lipogenesis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D000960:Hypolipidemic Agents; D047493:PPAR alpha; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D011345:Fenofibrate