Sirt1-PPARS Cross-Talk in Complex Metabolic Diseases and Inherited Disorders of the One Carbon Metabolism.
Study Goal
The researchers aimed to investigate the role of Sirtuin1 (Sirt1) in metabolic disorders induced by a high-fat diet, focusing on its impact on inflammation, insulin signaling, and fetal programming.
Results Summary
The study found that Sirt1 overexpression attenuates inflammation and macrophage infiltration caused by a high-fat diet, while its decreased expression contributes to metabolic syndrome, diabetes, and cardiovascular diseases. Preclinical studies of Sirt1 agonists showed mixed results in treating metabolic disorders.
Population
Obese patients, preclinical models (rats), and individuals with inherited vitamin B12 metabolism disorders.
Effective Dosage
Not specified
Duration
Not specified
Interactions
None mentioned
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
obesity | decrease | Sirt1 expression | obese patients | - | decreased | #1 |
weight loss | increase | Sirt1 expression | - | - | increased | #2 |
decreased Sirt1 expression | neutral | metabolic syndrome, diabetes mellitus type 2 (DT2), cardiovascular diseases and nonalcoholic liver disease | - | - | explains part of the pathomechanisms | #3 |
Sirt1 overexpression | decrease | inflammation and macrophage infiltration | - | - | attenuates | #4 |
high fat diet | increase | inflammation and macrophage infiltration | - | - | induced | #5 |
deficit in vitamin B12 and folate during pregnancy and lactation | decrease | decreased Sirt1 expression | heart, liver and brain of rat | - | produced | #6 |
impaired cellular availability of vitamin B12 | decrease | decreased expression of Sirt1 | - | - | produced | #7 |
Sirt1 agonists | no change | treatment of the metabolic syndrome | - | - | have produced contrasted results | #8 |
Sirt1 agonists | neutral | treatment of inherited disorders of vitamin B12 metabolism | - | - | has produced promising results | #9 |
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.