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

Abstract

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.

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

“…These mice express catalytically inactive SIRT1 (exon 4 deletion) under the control of the albumin promoter; thus, SIRT1 activity is lost exclusively in the liver (Purushotham et al., 2009). In young SIRT1 knockout (KO) hepatocytes at 3 months of age, cell viability after 2 hr of I/R was significantly lower than wild‐type (WT) cells (Figure 3e).…”

“…However, the acetylation status of other putative SIRT1 targets such as MFN1, VDAC, FOXO1, FOXO3A, mitoNEET, and PGC1α was not altered by SIRT1 overexpression (Figure S3). Note a visible co‐immunoprecipitation in SIRT1 KO cells due to the presence of a truncated form of SIRT1 in the liver (Purushotham et al., 2009). Collectively, these data suggest that the interaction between SIRT1 and MFN2 declines with aging, leading to enriching acetylated MFN2 in old hepatocytes.…”

“…All animal work was performed under the approval of the Institutional Care and Use Committee of the University of Florida. Mice with liver‐specific deletion of functional SIRT1 carry SIRT1 allele floxed exon 4 and express the Cre recombinase driven by the albumin promoter, as previously described (Purushotham et al., 2009). …”

Sirtuins and inflammation: Friends or foes?

“…A similar question has been elegantly addressed by Li's team, who focused on SIRT1's role in maintaining liver homeostasis. In two successive papers, Li's team has knocked out SIRT1 expression in hepatocytes [28] and in macrophages [29], and has assessed how this would affect liver steatosis following a HFD. Purushotham's liver specific SIRT1-KO mice (LKO) have impaired lipid homeostasis and are more prone to developing liver steatosis when fed a HFD, as compared to wt littermates [28] .…”

“…In two successive papers, Li's team has knocked out SIRT1 expression in hepatocytes [28] and in macrophages [29], and has assessed how this would affect liver steatosis following a HFD. Purushotham's liver specific SIRT1-KO mice (LKO) have impaired lipid homeostasis and are more prone to developing liver steatosis when fed a HFD, as compared to wt littermates [28] . Steatosis is accompanied by liver inflammation, with an increase in TNF and IL-1 synthesis and in total macrophage markers such as F4.80.…”