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Pathway Description
Fenofibrate Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2022-04-05
Last Updated: 2023-10-25
Fenofibrate is a peroxisome proliferator receptor alpha activator used to treat primary hypercholesterolemia, mixed dyslipidemia, severe hypertriglyceridemia. Fenofibrate acts in the nucleus where is activates the peroxisome proliferator-activated receptor alpha (PPARα). PPARα binds to the retinoic acid receptor alpha (RXRα). This PPARα-RXRα complex regulate gene transcription/translation of proteins and enzymes involved lipolysis, fatty acid transport and biosynthesis, vLDL and HDL synthesis.
Fatty acid biosynthesis is decreased due to the decrease expression of the enzyme acetyl-coA carboxylase. This enzyme is involved in one of the first steps in fatty acid synthesis by converting acetyl-coA to malonyl coA.
Fatty acid uptake from the plasma into the liver is increased. This is because there is an upregulation of the fatty acid transporter. This decreases the amount of circulating fatty acids. Fatty acid metabolism is also increased due to upregulation of acyl coA synthase, an enzyme involved in fatty acid oxidation. These 3 alterations ultimately decrease fatty acids in the body, making less fatty acids available for triglyceride synthesis.
Fenofibrate also increases HDL synthesis by upregulating apolipoprotein A1 (APOA1) and apolipoproteins A2 (APOA2), which forms part of HDL. HDL is considered good cholesterol.
VLDL and LDL are considered bad cholesterol. These levels are decreased due to downregulation of APOB which forms part of triglyceride-rich vLDL and LDL.
Finally, triglyceride levels are decreased by 30%-60% via upregulation of lipoprotein lipase (LPL). LPL hydrolyses triglyceride, thus breaking it down. Other proteins that affect LPL are also altered. For instance, APOA5 activates LPL and it’s expression is increased with fenofibrate. APOC3 inhibits lipolysis by inhibiting LPL, therefore, fenofibrate decreases the expression of APOC3.
Overall, fenofibrate lowers LDL-C, total-C, triglycerides, and Apo B, while increasing HDL-C.
Fenofibrate capsules and tablets are administered orally once daily with or without food. Some of the most common adverse effects associated with fibrates include headache, dizziness, back pain, joint pain, diarrhea, dyspepsia, cough, wheezing, nasopharyngitis, and flu-like symptoms.
References
Fenofibrate Pathway References
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