SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase

Author(s): Hou X, Xu S, Toolan KM, Sato K, Jiang B, et al.


Resveratrol may protect against metabolic disease through activating SIRT1 deacetylase. Because we have recently defined AMPK activation as a key mechanism for the beneficial effects of polyphenols on hepatic lipid accumulation, hyperlipidemia, and atherosclerosis in type 1 diabetic mice, we hypothesize that polyphenol-activated SIRT1 acts upstream of AMPK signaling and hepatocellular lipid metabolism. Here we show that polyphenols, including resveratrol and the synthetic polyphenol S17834, increase SIRT1 deacetylase activity, LKB1 phosphorylation at Ser428, and AMPK activity. Polyphenols substantially prevent the impairment in phosphorylation of AMPK and its downstream target, ACC (acetyl-CoA carboxylase), elevation in expression of FAS (fatty acid synthase), and lipid accumulation in human HepG2 hepatocytes exposed to high glucose. These effects of polyphenols are largely abolished by pharmacological and genetic inhibition of SIRT1, suggesting that the stimulation of AMPK and lipid-lowering effect of polyphenols depend on SIRT1 activity. Furthermore, adenoviral overexpression of SIRT1 stimulates the basal AMPK signaling in HepG2 cells and in the mouse liver. AMPK activation by SIRT1 also protects against FAS induction and lipid accumulation caused by high glucose. Moreover, LKB1, but not CaMKKβ, is required for activation of AMPK by polyphenols and SIRT1. These findings suggest that SIRT1 functions as a novel upstream regulator for LKB1/AMPK signaling and plays an essential role in the regulation of hepatocyte lipid metabolism. Targeting SIRT1/LKB1/AMPK signaling by polyphenols may have potential therapeutic implications for dyslipidemia and accelerated atherosclerosis in diabetes and age-related diseases.

Similar Articles

Visceral obesity, hypertension and cardio-renal risk: a review

Author(s): Rosa E, Zanella M, Ribeiro A, Kohlmann Junior O

Nonalcoholic fatty liver disease decrease in obese adolescents after multidisciplinary therapy

Author(s): Tock L, Prado W, Caranti D, Cristofalo D, Lederman H, et al.

Obesity and cardiovascular diseases

Author(s): Kachur S, Lavie C, Schutter A, Milani R, Ventura H

Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis

Author(s): Marra F, Gastaldelli A, Baroni G, Tell G, Tiribelli C

Brown versus white adipose tissue: A mini-review

Author(s): Saely C, Geiger K, Drexel H

Inflammatory mechanisms in obesity

Author(s): Gregor M, Hotamisligil G

Swimming training beneficial effects in a mice model of nonalcoholic fatty liver disease

Author(s): Schultz A, Mendonca L, Aguila M, Mandarim-de-Lacerda C

Improved hepatic lipid composition following short-term exercise in nonalcoholic fatty liver disease

Author(s): Haus J, Solomon T, Kelly K, Fealy C, Kullman E, et al.

Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome

Author(s): Tjønna A, Lee S, Rognmo Ø, Stølen, T, Bye A, et al.

Exercise Effects on White Adipose Tissue: Beiging and Metabolic Adaptations

Author(s): Stanford K, Middelbeek R, Goodyear L

Nitric oxide synthesis blockade increase hypertrophy and cardiac fibrosis in rats submitted to aerobic training

Author(s): Souza HC, Penteado DM, Martin-Pinge M, Barbosa N, Teixeira Vde P et al.

Anthropometrical parameters and markers of obesity in rats

Author(s): Novellie Y, Galhardi C, Ebaid G, Rodrigues H, Mani F

N-acetylcysteine prevents development of the hyperdynamicciculation in the portal hypertensive rat

Author(s): Fernando B, Marley R, Holt S, Anand R, Harry D, et al.

C1q: structure, function, and receptors

Author(s): Kishore U, Reid K

FNDC5 and irisin in humans: I

Author(s): Huh J, Panagiotou G, Mougios V, Brinkoetter M, Vamvini M, et al.

Reversibility of chronic experimental syndrome X by diet modification

Author(s): Roberts C, Vaziri N, Liang K and Barnard R

Exercise reverses metabolic syndrome in high-fat diet-induced obese rats

Author(s): Touati S, Meziri F, Devaux S, Berthelot A, Touyz R, Laurant P

Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds

Author(s): Struben VM, Hespenheide EE, Caldwell SH

Impact of cholesterol metabolism and the LXRα-SREBP-1c pathway on nonalcoholic fatty liver disease

Author(s): Nakamuta M, Fujino T, Yada R, Yada M, Yasutake K, et al.

NASH and atherosclerosis are two aspects of a shared disease: Central role for macrophages

Author(s): Bieghs V, Rensen P, Hofker M, Shiri-Sverdlov R

Long‐term follow‐up of patients with NAFLD and elevated liver enzymes

Author(s): Ekstedt M, Franzén L, Mathiesen U, Thorelius L, Holmqvist M, et al.

Oxidative Stress in Obesity: A Critical Component in Human Diseases

Author(s): Marseglia L, Manti S, D’Angelo G, Nicotera A, Parisi E, et al.

Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance

Author(s): Moreno-Navarrete J, Ortega F, Serrano M, Guerra E, Pardo G, et al.

Fructose as a key player in the development of fatty liver disease

Author(s): Basaranoglu M, Basaranoglu G, Sabuncu T, Sentürk H

How much is too much? Interleukin-6 and its signalling in atherosclerosis

Author(s): Schuett H, Luchtefeld M, Grothusen C, Grote K, Schieffer B

Leptin: molecular mechanisms, systemic pro-inflammatory effects and clinical implications

Author(s): Paz-Filho G, Mastronardi C, Franco C, Wang K, Wong M, et al.

Multiple mechanisms involved in obesity-induced hypertension

Author(s): Antic V, Dulloo A, Montani J

Leptin and cardiovascular disease

Author(s): Koh K, Park S, Quon M

Challenges and opportunities of defining clinical leptin resistance

Author(s): Myers M, Heymsfield S, Haft C, Kahn B, Laughlin M, et al.

Irisin is inversely associated with intrahepatic triglyceride contents in obese adults

Author(s): Zhang H, Zhang X, Ma Z, Pan L, Chen Z, et al.

Exercise training increases lipid metabolism gene expression in human skeletal muscle

Author(s): Tunstall R, Mehan K, Wadley G, Collier G, Bonen A, et al.

Weight loss in combination with physical activity improves endothelial dysfunction in human obesity

Author(s): Sciacqua A, Candigliota M, Ceravolo R, Scozzafava A, Sinopoli F, et al.

Exercise, adipokines and pediatric obesity: a meta-analysis of randomized controlled trials

Author(s): García-Hermoso A, Ceballos-Ceballos R, Poblete-Aro C, Hackney A, Mota J, et al.

A PGC1-[agr]-dependent myokine that drives brown-fat-like development of white fat and thermogenesis

Author(s): Boström P, Wu J, Jedrychowski M, Korde A, Ye L, et al.

Irisin, turning up the heat

Author(s): Villarroya F

Assessment of inflammatory and oxidative biomarkers in obesity and their associations with body mass index

Author(s): Piva S, Tatsch E, De Carvalho J, Bochi G, Kober H, et al.

Impairment of insulin signaling in human skeletal muscle cells by co-culture with human adipocytes

Author(s): Dietze D, Koenen M, Röhrig K, Horikoshi H, Hauner H, et al.

Irisin, a link among fatty liver disease, physical inactivity and insulin resistance

Author(s): Arias-Loste M, Ranchal I, Romero-Gómez M, Crespo J