Emerging roles of SIRT1 in fatty liver diseases

Abstract

Fatty liver diseases, which are commonly associated with high-fat/calorie diet, heavy alcohol consumption and/or other metabolic disorder causes, lead to serious medical concerns worldwide in recent years. It has been demonstrated that metabolic homeostasis disruption is most likely to be responsible for this global epidemic. Sirtuins are a group of conserved nicotinamide adenine dinucleotide (NAD⁺) dependent histone and/or protein deacetylases belonging to the silent information regulator 2 (Sir2) family. Among seven mammalian sirtuins, sirtuin 1 (SIRT 1) is the most extensively studied one and is involved in both alcoholic and nonalcoholic fatty liver diseases. SIRT1 plays beneficial roles in regulating hepatic lipid metabolism, controlling hepatic oxidative stress and mediating hepatic inflammation through deacetylating some transcriptional regulators against the progression of fatty liver diseases. Here we summarize the latest advances of the biological roles of SIRT1 in regulating lipid metabolism, oxidative stress and inflammation in the liver, and discuss the potential of SIRT1 as a therapeutic target for treating alcoholic and nonalcoholic fatty liver diseases.

Keywords: fatty acid β-oxidation; fatty liver diseases; inflammation.; lipogenesis; oxidative stress.

Figure 1

Fatty liver diseases are initiated by aberrant hepatic lipid metabolism, and sirtuin 1 (SIRT1) activation plays beneficial effect against the process through inhibiting de novo lipogenesis and increasing fatty acid β-oxidation. Liver steatosis is the initial stage of fatty liver diseases, which is characterized by excessive triglyceride (TG) deposition as lipid droplets in the liver. Lipid metabolism is tightly linked with dietary fat, calorie and alcohol intake, which could be subsequently digested and convert to circulating TG-rich chylomicrons, free fatty acid (FFA), glucose, insulin and so on. Circulating TG-rich chylomicrons and free fatty acid (FFA) could be uptaken by liver through transmembrane proteins. High levels of circulating glucose and insulin could stimulate de novo lipogenesis activating transcription factors carbohydrate response element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c), followed by activating their downstream lipogenic enzymes including fatty acid synthase (FAS), acetyl-CoA carboxylase 1 (ACC1), stearoyl-CoA desaturase-1 (SCD1) and elongase of long chain fatty acids family 6 (ELOVL6) to synthesize FFA and TG in the liver. In order to maintain lipid homeostasis, there are also two removal pathways for acquired FFA and TG, including metabolizing FFA through fatty acid β-oxidation in mitochondria via peroxisome proliferator-activated receptor alpha (PPARα) / peroxisome proliferator-activated receptor-gamma co-activator 1 alpha (PGC-1α) signaling, and secreting TG into blood circulation as the form of very low-density lipoprotein (VLDL). Under high-fat diet, high-calorie diet and/or heavy alcohol intake condition, excessive lipid acquisition usually is stimulated through increasing lipid uptake and/or lipogenesis, meanwhile lipid removal pathway could also be impaired by decreasing fatty acid β-oxidation and/or VLDL secretion. Together, the imbalance of hepatic TG/fatty acids flux acquisition and removal consequently cause steatosis in the liver. During the process, SIRT1 activation shows beneficial effect through inhibiting lipogenesis by deacetylating SREBP-1c and ChREBP to block their downstream lipogenic genes, and increasing fatty acid β-oxidation via deacetylating PPARα/PGC-1α, thus rebalances the hepatic lipid hemostasis.

Figure 2

Accumulated hepatic oxidative stress and inflammation promote fatty liver diseases progression, and SIRT1 activation plays beneficial effect against diseases progression. Accumulated lipid droplets in the liver will trigger further hepatic oxidative and inflammation, which subsequently develop a continued liver damage process. The excessive hepatic oxidative stress and inflammation are characterized by abundant reactive oxygen species (ROS) production and large cytokine production, particularly tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). Additionally, adipose tissue also contributes to the diseases aggravation by secreting FFA and inflammatory cytokines to circulation, which further could be delivered to liver. During fatty liver diseases progression, SIRT1 activation plays beneficial roles on defending hepatic oxidative stress through enhancing antioxidant capability involving fork head box proteins (FOXOs) and PGC-1α deacetylation, and reducing pro-inflammatory cytokines production through deacetylating nuclear factor-κB (NF-κB) both in the liver and in the adipose tissue. In addition to beneficial effect, SIRT1 activation also possesses a contradictory role in adipose tissue-liver axis, which might exacerbate fatty liver formation. Under SIRT1 activation, transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ) is repressed and FOXO1/ adipose triglyceride lipase (ATGL) signaling is activated, which promote lipolysis of adipose tissue to increase large amount of FFA fluxing to circulation, later might be uptaken by liver.

Figure 3

SIRT1 liver-specific knockout causes liver steatosis. (A) Summary of fatty liver cases at different age among control (Sirt1^flox5-6) and liver-specific SIRT1 knockout (Sirt1^LKO) male mice. (B) Oil Red O staining of 14 months old male liver with higher magnification. (C-E) Liver TG content (C), plasma FFA amount (D) and plasma TG content (E) of 9 months old male mice (n=11). *p<0.05. (Adapted from Wang et al. 2010 68)