Sirtuin 6-A Key Regulator of Hepatic Lipid Metabolism and Liver Health

Abstract

Sirtuin 6 (SIRT6) is an NAD-dependent deacetylase/deacylase/mono-ADP ribosyltransferase, a member of the sirtuin protein family. SIRT6 has been implicated in hepatic lipid homeostasis and liver health. Hepatic lipogenesis is driven by several master regulators including liver X receptor (LXR), carbohydrate response element binding protein (ChREBP), and sterol regulatory element binding protein 1 (SREBP1). Interestingly, these three transcription factors can be negatively regulated by SIRT6 through direct deacetylation. Fatty acid oxidation is regulated by peroxisome proliferator activated receptor alpha (PPARα) in the liver. SIRT6 can promote fatty acid oxidation by the activation of PPARα or the suppression of miR-122. SIRT6 can also directly modulate acyl-CoA synthetase long chain family member 5 (ACSL5) activity for fatty acid oxidation. SIRT6 also plays a critical role in the regulation of total cholesterol and low-density lipoprotein (LDL)-cholesterol through the regulation of SREBP2 and proprotein convertase subtilisin/kexin type 9 (PCSK9), respectively. Hepatic deficiency of Sirt6 in mice has been shown to cause hepatic steatosis, inflammation, and fibrosis, hallmarks of alcoholic and nonalcoholic steatohepatitis. SIRT6 can dampen hepatic inflammation through the modulation of macrophage polarization from M1 to M2 type. Hepatic stellate cells are a key cell type in hepatic fibrogenesis. SIRT6 plays a strong anti-fibrosis role by the suppression of multiple fibrogenic pathways including the transforming growth factor beta (TGFβ)-SMAD family proteins and Hippo pathways. The role of SIRT6 in liver cancer is quite complicated, as both tumor-suppressive and tumor-promoting activities have been documented in the literature. Overall, SIRT6 has multiple salutary effects on metabolic homeostasis and liver health, and it may serve as a therapeutic target for hepatic metabolic diseases. To date, numerous activators and inhibitors of SIRT6 have been developed for translational research.

Keywords: SIRT6; fatty acid oxidation; fibrosis; hepatocellular carcinoma; inflammation; lipogenesis; modulator.

Figure 1

Schematic diagram of the human SIRT6 protein domain structure. SIRT6 protein can be divided into three domains: N-terminal, central, and C-terminal.

Figure 2

Human and mouse SIRT6 peptide sequence alignments. The longest isoforms of human and mouse SIRT6 proteins were aligned using the Clustal Omega multiple sequence alignment tool on the EMBL-EBI website.

Figure 3

Regulation of hepatic triglycerides and cholesterol by SIRT6. Several master regulators for triglyceride biosynthesis, including LXR, ChREBP, SREBP1, and XBP1, can be suppressed by SIRT6 through deacetylation. SIRT6 can be recruited to the promoter of the SREBP2 gene through FOXO3 transcription factor to suppress hepatic cholesterol biosynthesis. Additionally, SIRT6 and FOXO3 also suppress the PCSK9 gene transcription to reduce LDL-cholesterol in the blood circulation.

Figure 4

SIRT6 promotes fatty acid oxidation by multiple mechanisms. In the nucleus, SIRT6 can induce FAO genes through the regulation of NCOA2 and PPARα or indirectly promotes FAO through the inhibition of the CREBH transcriptional activation of the CIDEC gene or the miR-122 gene transcription. In the cytoplasm, palmitate-bound SIRT6 can deacetylate ACSL5 to directly increase the ACSL5 enzymatic activity by converting long-chain fatty acids to long-chain fatty acyl-CoAs.

Figure 5

SIRT6 protects against liver injury. SIRT6 has multiple mechanisms for defending against oxidative stress, including the induction of ENDOG and MT1/2 and the activation of NRF2. SIRT6 can activate FXR and NRF2 to alleviate APAP-induced liver injury. Intrahepatic bile acid accumulation may cause cholestasis. SIRT6 can suppress ERRγ-mediated bile acid biosynthesis to reduce bile acid-induced liver injury.

Figure 6

SIRT6 modulates hepatic inflammation. Specifically, SIRT6 can suppress M1 macrophage polarization by the inhibition of NF-κB and STAT3 activities and represses c-JUN-mediated inflammatory genes.

Figure 7

SIRT6 has an anti-fibrosis function. SIRT6 can control hepatic fibrosis by the suppression of the TGFβ-SMAD and YAP/TAZ pathways through deacetylation.

Figure 8

The role of SIRT6 in liver cancer. The top panel describes the anti-cancer functions of SIRT6. SIRT6 can suppress tumor-promoting factors through either gene repression by the deacetylation of histone H3 or the suppression of an intermediate factor such as hnRNPA1. The bottom panel describes the tumor-promoting activities of SIRT6. AKT and ERK have been shown to be activated by SIRT6, although the mechanisms remain unclear. In some conditions, SIRT6 may also inhibit some tumor suppressors such as CDH1 and FOXO3.