Hepatocyte-specific Deletion of SIRT1 Alters Fatty Acid Metabolism and Results in Hepatic Steatosis and Inflammation

By A. Purushotham, T. Schug, Qing Xu, S. Surapureddi, Xiumei Guo, Xiaoling Li. Cell Metabolism, 2009

1,100 citations recorded by the source corpus.

SUMMARY Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. SIRT1, a NAD+-dependent protein deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. Here we demonstrate that hepatic SIRT1 regulates lipid homeostasis by positively regulating PPARα, a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of SIRT1 impairs PPARα signaling and decreases fatty acid β-oxidation, whereas overexpression of SIRT1 induces the expression of PPARα targets. SIRT1 interacts with PPARα and is required to activate PPARα co-activator PGC-1α. When challenged with a high-fat diet, liver-specific SIRT1 knockout mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress. Taken together, our data indicate that SIRT1 plays a vital role in the regulation of hepatic lipid homeostasis, and that pharmacological activation of SIRT1 may be important for the prevention of obesity-associated metabolic diseases.

Subfields: Cell Biology, Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/d460195c0cf0fa339372330d69704d2bd6a4c7d4

How researchers see this paper

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In Cell Biology

1. Herbert Tilg
2. U. Albrecht
3. A. Moschen

In Geriatrics and Gerontology

1. Hung-Chun Chang
2. U. Albrecht
3. L. Guarente
4. D. Sinclair
5. M. Haigis
6. Johan Auwerx
7. E. Verdin
8. E. Seto

In Physiology

1. Hung-Chun Chang
2. U. Albrecht
3. Herbert Tilg
4. L. Guarente
5. A. Moschen
6. D. Sinclair
7. M. Haigis
8. C. Kenyon

Citations in the corpus

• Timing to perfection: the biology of central and peripheral circadian clocks. (2012, background): “Interestingly, SIRT1 also affects the activity of other transcription factors such as PPARa (Purushotham et al., 2009) and coactivator PGC-1a (Rodgers et al., 2005), highlighting another avenue for the modulation of circadian gene expression and metabolism in the liver.”
• Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis (2010, background): “Hepatocyte-specific deletion of Sirt1 leads not only to hepatic steatosis but also to ER stress and liver inflammation.(58) Genetically obese leptin-deficient ob/ob mice exhibit a reversal of the Fig.”
• Energy Metabolism in the Liver (2014, neutral): “and exacerbates diet-induced steatosis (216).”
• SIRT1 and other sirtuins in Metabolism (2013, background): “The result is repression of fat and cholesterol synthesis, consistent with the finding that SIRT1 liver-specific knockout mice develop hepatic steatosis [58].”