Skip to Content
Merck

SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPARα.

Cell reports (2019-12-19)
Shoshana Naiman, Frank K Huynh, Reuven Gil, Yair Glick, Yael Shahar, Noga Touitou, Liat Nahum, Matan Y Avivi, Asael Roichman, Yariv Kanfi, Asaf A Gertler, Tirza Doniger, Olga R Ilkayeva, Ifat Abramovich, Orly Yaron, Batia Lerrer, Eyal Gottlieb, Robert A Harris, Doron Gerber, Matthew D Hirschey, Haim Y Cohen
ABSTRACT

The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPARα signaling, known to regulate multiple metabolic pathways. SIRT6 binds PPARα and its response element within promoter regions and activates gene transcription. Sirt6+/- results in significantly reduced PPARα-induced β-oxidation and its metabolites and reduced alanine and lactate levels, while inducing pyruvate oxidation. Reciprocally, starved SIRT6 transgenic mice show increased pyruvate, acetylcarnitine, and glycerol levels and significantly induce β-oxidation genes in a PPARα-dependent manner. Furthermore, SIRT6 mediates PPARα inhibition of SREBP-dependent cholesterol and triglyceride synthesis. Mechanistically, SIRT6 binds PPARα coactivator NCOA2 and decreases liver NCOA2 K780 acetylation, which stimulates its activation of PPARα in a SIRT6-dependent manner. These coordinated SIRT6 activities lead to regulation of whole-body respiratory exchange ratio and liver fat content, revealing the interactions whereby SIRT6 synchronizes various metabolic pathways, and suggest a mechanism by which SIRT6 maintains healthy liver.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ethidium bromide solution, BioReagent, for molecular biology, 10 mg/mL in H2O
SKU
Pack Size
Availability
Price
Quantity
SAFC
Formaldehyde solution, contains 10-15% methanol as stabilizer, 37 wt. % in H2O
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Magnesium sulfate heptahydrate, ReagentPlus®, ≥99.0%
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Anti-Cy5 antibody, Mouse monoclonal, clone CY5-15, purified from hybridoma cell culture
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Monoclonal Anti-α-Tubulin antibody produced in mouse, ascites fluid, clone B-5-1-2
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Dexamethasone-Water Soluble, suitable for cell culture, BioReagent
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Carboxymethylcellulose sodium salt, Medium viscosity
SKU
Pack Size
Availability
Price
Quantity