Sirt1-PPARS Cross-Talk in Complex Metabolic Diseases and Inherited Disorders of the One Carbon Metabolism

Abstract

Sirtuin1 (Sirt1) has a NAD (+) binding domain and modulates the acetylation status of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and Fork Head Box O1 transcription factor (Foxo1) according to the nutritional status. Sirt1 is decreased in obese patients and increased in weight loss. Its decreased expression explains part of the pathomechanisms of the metabolic syndrome, diabetes mellitus type 2 (DT2), cardiovascular diseases and nonalcoholic liver disease. Sirt1 plays an important role in the differentiation of adipocytes and in insulin signaling regulated by Foxo1 and phosphatidylinositol 3′-kinase (PI3K) signaling. Its overexpression attenuates inflammation and macrophage infiltration induced by a high fat diet. Its decreased expression plays a prominent role in the heart, liver and brain of rat as manifestations of fetal programming produced by deficit in vitamin B12 and folate during pregnancy and lactation through imbalanced methylation/acetylation of PGC1α and altered expression and methylation of nuclear receptors. The decreased expression of Sirt1 produced by impaired cellular availability of vitamin B12 results from endoplasmic reticulum stress through subcellular mislocalization of ELAVL1/HuR protein that shuttles Sirt1 mRNA between the nucleus and cytoplasm. Preclinical and clinical studies of Sirt1 agonists have produced contrasted results in the treatment of the metabolic syndrome. A preclinical study has produced promising results in the treatment of inherited disorders of vitamin B12 metabolism.

Mechanisms Mediating the Regulation of Peroxisomal Fatty Acid Beta-Oxidation by PPARα

“…Numerous findings provide evidence that natural ligands exhibit different binding affinities, which subsequently impact PPARα activation potency. Previous reports showed that omega-3 eicosapentaenoic acid (20:5, ω3) and, to a lesser extent, docosahexaenoic acid (22:6, ω3), are potent ligands [96,97] and consistent activators of PPARα [98][99][100], while omega-3 PUFA like linolenic acid (C18:3, ω3) and docosapentaenoic (22:5, ω3) acids, and omega-6 PUFA such as linoleic (C18:2, ω6) and arachidonic (C20:4, ω6) acids are weaker PPARα activators [74,99,100]. In addition, experiments performed by Ellinghaus et al and Zomer et al [101,102] revealed that phytanic acid (3,7,11,15-tertamethylhexadecanoic acid) is a strong natural physiological ligand for PPARα.…”

“…Essential coregulators are proteins deemed critical for the survival of the offspring, and their absence results in embryonic lethality: cAMP-response element-binding protein (CBP); PPAR-interacting protein/activating signal cointegrator 2 (PRIP/ASC2); PPAR-binding protein/mediator complex subunit 1 (PBP/Med1); mediator complex subunit 25 (Med25) [131][132][133]. Non-essential coregulators are proteins with such critical functional responsibilities that they are usually represented by more than one isoform-steroid receptor coactivators (SRCs) [131,132,134], Asp-Glu-Ala-Asp (DEAD)-box helicases [135][136][137], sirtuins (SIRT) [96,97], PPARγ coactivators (PGCs) [138][139][140][141]-and the loss of one isoform is compensated by others. Repressors that bind to the nuclear receptor PPARα in the absence of/or independent of ligands prevent it from binding to the peroxisomal proliferator response elements (PPRE) of the target genes as nuclear corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone (SMRT) [96] (Figure 7A).…”

“…The ligand binding to a nuclear receptor triggers a molecular switch that releases corepressors and begins the recruitment of coactivator complexes, such as members of the CBP/p300 family, which exhibit the histone acetyltransferase activity required to facilitate chromatin remodeling. The subsequent recruitment of other coregulators, either singly or as preassembled multisubunit protein complexes, including mediator complex and RNA polymerase machinery, is facilitated by the interaction of the general basal transcription machinery to enhance the transcription of a specific set of genes [97,168]. As discussed previously, coregulators contain an LXXLL motif that forms two turns of the α-helix and binds to a hydrophobic cleft on the surface of the nuclear receptor.…”

PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases

“…Finally, the use of liver-specific PPAR-null mice has opened the possibility of studying other important mechanisms in which PPARs are involved [ 149 ], mainly as mediators of epigenetic regulation mechanisms through their interaction with enzymes such as Sirtuin-1 [ 32 , 150 ], the regulation of PPAR promoters, through DNA methyltransferases (DNMTs) [ 151 ], and the regulation of their expression through a variety of microRNAs [ 152 ].…”

Relieving Cellular Energy Stress in Aging, Neurodegenerative, and Metabolic Diseases, SIRT1 as a Therapeutic and Promising Node

“…SIRT1 is widely involved in the metabolic control of intracellular substrates in the body. The decrease of SIRT1 expression and activity is a major characteristic of metabolic diseases, and its mechanism partly explains the influence of a high-fat diet on metabolic syndrome, obese diabetes, cardiovascular disease, and other related metabolic diseases (Kosgei et al, 2020 ). Decrease of SIRT1 expression can also lead to lipid accumulation and impaired insulin signaling in hepatocytes.…”