Peroxisome proliferator-activated receptor α attenuates high-cholesterol diet-induced toxicity and pro-thrombotic effects in mice

Abstract

Peroxisome proliferator-activated receptor α (PPARα) is involved in the regulation of fatty acid and cholesterol metabolism. A high-cholesterol (HC) diet increases the risk of developing cardiovascular diseases (CVD); however, it is unclear whether the toxic effects of cholesterol involve changes in thrombotic factor expression, and whether PPARα is necessary for such effects. To investigate this possibility, we fed a HC diet to wild-type (WT) and Ppara-null mice and measured cholesterol and triglyceride contents, liver histology, serum/plasma levels of coagulation factors, hepatic expression of the coagulation factors, liver/serum sulfatide levels, hepatic sulfatide metabolism, hepatic expression of lipid transporters, and hepatic oxidative stress and its relating enzymes. In Ppara-null mice, the HC diet caused triglyceride accumulation and exacerbated inflammation and oxidative stress in liver, increased levels of coagulation factors, including tissue factor, plasminogen activator inhibitor-1 and carboxypeptidase B2 in blood and liver, and decreased levels of anti-thrombotic sulfatides in serum and liver. These changes were much less marked in WT mice. These findings imply that cholesterol overload exerts its toxic effects at least in part by enhancing thrombosis, secondary to abnormal hepatic lipid metabolism, inflammation, and oxidative stress. Moreover, we reveal for the first time that PPARα can attenuate these toxic effects by transcriptional regulation of coagulation factors and sulfatides, in addition to its known effects of controlling lipid homeostasis and suppressing inflammation and oxidative stress. Therapies aimed at activating PPARα might prevent HC diet-induced CVD through modulating various pro- and anti-thrombotic factors.

Coagulopathy in Malnourished Mice Is Sexually Dimorphic and Regulated by Nutrient‐Sensing Nuclear Receptors

“…These data add to growing evidence that PPARα contributes to the regulation of coagulation factor synthesis. A recent study found that deletion of PPARα worsens the prothrombotic effect of a high‐cholesterol diet through increased synthesis of several coagulation factors, ( 32 ) and earlier work illustrates that PPARα decreases fibrinogen‐β expression by directly binding to a DNA response element and interfering with a transcriptional coactivator complex. ( 33 ) Indeed, one might speculate that decreasing coagulation factor synthesis thereby reducing thrombotic potential could contribute to some of the benefits of fibrates in cardiovascular diseases.…”

Madecassoside Inhibits Body Weight Gain via Modulating SIRT1-AMPK Signaling Pathway and Activating Genes Related to Thermogenesis

“…And PGC-1a acts as a key regulator of mitochondrial biogenesis and function, PPARa is involved in regulating fatty acid and cholesterol metabolism, and CPT 1A is an enzyme that is anchored to the outer mitochondrial membrane (OMM), and it regulates the passage of fatty acids into the mitochondria and interferes with boxidation of long-chain fatty acids. These three factors play an important role in the occurrence of fatty acid oxidation (38)(39)(40). So, these three factors were tested and shown in Figure 7.…”

Integrative Analysis Reveals Subtype-Specific Regulatory Determinants in Triple Negative Breast Cancer

“…PPARA and PPARG ligands, known as peroxisome proliferators, have been shown to induce cell cycle arrest at the G1 phase of the cell cycle to prompt the differentiation of liposarcoma, colon, prostate and BC cells, conferring a less malignant phenotype to the cells [28]. PPARA and PPARG are also involved in the regulation of cholesterol metabolism [48], which was shown to regulate cell adhesion in breast cancer cell lines [49].…”