Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas

Abstract

Coronavirus disease 2019 (COVID-19) has several extrapulmonary symptoms. Gastrointestinal (GI) symptoms are among the most frequent clinical manifestations of COVID-19, with severe consequences reported in elderly patients. Furthermore, the impact of COVID-19 on patients with pre-existing digestive diseases still needs to be fully elucidated, particularly in the older population. This review aimed to investigate the impact of COVID-19 on the GI tract, liver, and pancreas in individuals with and without previous digestive diseases, with a particular focus on the elderly, highlighting the distinctive characteristics observed in this population. Finally, the effectiveness and adverse events of the anti-COVID-19 vaccination in patients with digestive disorders and the peculiarities found in the elderly are discussed.

Accumulation of Linoleic Acid by Altered Peroxisome Proliferator-Activated Receptor-α Signaling Is Associated with Age-Dependent Hepatocarcinogenesis in Ppara Transgenic Mice

“…Diminished liver carcinogenesis has also been observed in PPARA -humanized mice after chronic administration of PPARα agonists demonstrating the mechanism of species differences in liver cancer between rodents and humans [ 13 , 14 , 16 ]. These observations coupled with a larger body of evidence indicate that rodents can develop liver cancer after chronic administration of PPARα agonist whereas humans do not [ 5 , 9 , 10 , 11 , 21 , 22 , 23 , 49 , 50 ]. Results from the present studies show that PPARα-dependent effects increase fatty acids, triglycerides, and monounsaturated fatty acids in the liver metabolome in wild-type mice, and are not found in similarly treated Ppara -null mice.…”

“…While there is strong evidence that PPARα is required to mediate liver carcinogenesis caused by chronic ligand activation of PPARα in rodents, there is equally convincing evidence that humans do not develop liver cancer following administration of PPARα agonists (reviewed in [ 5 , 9 , 10 , 11 , 21 , 22 , 49 , 50 ]). This is based on different types of studies ranging from retrospective and prospective studies showing no change in liver cancer in humans treated with PPARα ligands (e.g., fibrate drugs), to preclinical studies showing that Ppara -null and PPARA -humanized mice are refractory to liver carcinogenesis after long-term administration of PPARα agonists [ 5 , 9 , 13 , 14 , 15 , 16 , 21 , 22 ], and lack of increased proliferation of human hepatocytes in chimeric humanized mice [ 23 ].…”

“…It is important to note that PPARα is the molecular target that mediates the lipid lowering effects of the widely prescribed fibrate class of hypolipidemic drugs [ 9 ]. The mechanism by which PPARα causes a decrease in serum triglycerides by fibrates is primarily through increased expression of PPARα target genes that facilitate the transport of fatty acids across membranes and catabolism in tissues that generates cellular ATP via oxidation of long-chain fatty acids and effectively decreases the triglycerides in serum [ 9 , 10 , 11 ]. Since most organisms typically exist in a fasting state where fatty acids are higher and able to bind with PPARα, this nuclear receptor is essential for regulating lipid homeostasis [ 12 ].…”

“…While it is clear that PPARα activation is essential for cellular energy homeostasis [ 9 , 10 , 11 ], pharmacological activation of the PPARα with synthetic ligands causes hepatocarcinogenesis in rodents through a mechanism that requires PPARα. Whereas wild-type mice which were fed a diet with the synthetic PPARα ligands Wy-14,643, bezafibrate, or GW7647 all exhibited close to 100% incidence of liver cancer after approximately one year of treatment, Ppara -null mice are largely refractory to this effect [ 13 , 14 , 15 , 16 , 17 ].…”

Different Coactivator Recruitment to Human PPARα/δ/γ Ligand-Binding Domains by Eight PPAR Agonists to Treat Nonalcoholic Fatty Liver Disease

“…PPARs belong to the 1C class of the nuclear receptor (NR) superfamily and are ligand-activated transcription factors (TFs) that regulate the expression of multiple gene sets involved in metabolism [ 6 , 7 ]. Three cognate subtypes, namely, PPARα (NR1C1), PPARδ (also known as PPARß; NR1C2), and PPARγ (NR1C3), have been identified in mammals [ 8 ]. PPARα regulates lipid and glucose metabolism through the direct transcriptional control of genes involved in peroxisomal/mitochondrial oxidation, fatty acid uptake, and triglyceride catabolism [ 9 ].…”