In addition to glucose homeostasis, the liver plays important roles in controlling lipid and cholesterol homeostasis. During fasting, fat and cholesterol synthesis in the liver is turned off, and lipolysis in WAT is favored. The major hepatic transcription factors for lipogenesis and cholesterol synthesis are proteins belonging to the sterol regulatory element binding protein (SREBP) family [62]. Upon fasting, SIRT1 deacetylates SREBP1 and targets the protein for destruction through the ubiquitin–proteasome system (Figure 1) [63]. The result is repression of fat and cholesterol synthesis, consistent with the finding that SIRT1 liver-specific knockout mice develop hepatic steatosis [58]. For regulating cholesterol homeostasis, SIRT1 also regulates the oxysterol receptor (LXRα) to assist in reverse cholesterol transport from peripheral tissues by upregulating the LXRα target gene ATP-binding cassette transporter A1 (ABCA1) [64]. The cholesterol regulatory loop can be further modulated through the bile acid receptor, that is, farnesoid X receptor (FXR), which is important for biosynthesis of bile acids and cholesterol catabolic pathways. SIRT1 deacetylates and activates FXR [65], and FXR can also upregulate SIRT1 by repressing the SIRT1-targeting microRNA mir-34a [66]. Similarly, SIRT6 appears to regulate cholesterol levels by repressing SREBP1/2, both at the level of their expression and their post-translational cleavage into the active form [67, 68]. These results again point out collaborative roles of nuclear sirtuins, in this case in hepatic lipid metabolism. Finally, SIRT1 plays an important role in maintaining circadian regulation of metabolic processes in the liver by regulating the cell autonomous, circadian clock in that tissue [69, 70]. This regulation involves the deacetylation of two central components of the clock, BMAL1 (Brain and Muscle ARNT-Like 1) and PER2 (Period 2), in the liver.
Besides nuclear sirtuins, mitochondrial SIRT3 is critical in fatty acid oxidation in the mitochondria. Upon fasting or calorie restriction, SIRT3 protein level and activity are upregulated in mitochondria [26] to promote fatty acid oxidation via deacetylating long-chain-specific acyl coenzyme A dehydrogenase (LCAD) [71]. This sirtuin also activates the urea cycle [37] and ketogenesis in liver [72]. Interestingly, mitochondrial SIRT4 shows opposite activity to SIRT1 and SIRT3. SIRT4 depletion prevents steatosis upon high-fat diet feeding [73]. In addition, SIRT4 represses PPARα to inhibit fatty acid oxidation, meanwhile it also represses malonyl CoA decarboxylase 1 (MCD1) to support lipid synthesis [74]. Thus multiple sirtuins play many important roles in tuning liver metabolism to nutrient availability.
Metabolic regulation in the muscle and WAT
The switch from carbohydrate to lipid use for energy production is induced in skeletal muscle by exercise or fasting. When SIRT1 levels are elevated upon fasting, PGC-1α is deacetylated by this sirtuin to activate genes for fat oxidation (Figure 1) [75]. AMPK is also activated by energy depletion (resulting in higher AMP levels in cells) and drives the expression of the PGC-1α gene under these conditions [76]. The combined result is increased mitochondrial biogenesis and fatty acid oxidation in the muscle [75, 77]. The effect of SIRT1 and AMPK can also be amplified through a reciprocal positive regulatory loop. AMPK can increase NAD+ levels by upregulating nicotinamide phosphoribosyltransferase (NAMPT), one of the crucial enzymes for NAD biosynthesis [78, 79]. Reciprocally, SIRT1 can deacetylate the serine/threonine kinase liver kinase B1 (LKB1) to activate AMPK [80]. Muscle thus mediates an essential antidiabetic function by oxidizing fatty acids. The mitochondrial SIRT3 also drives oxidative metabolism in skeletal muscle as well as liver. SIRT3 deacetylates and activates pyruvate dehydrogenase (PDH), and loss of SIRT3 results in impaired oxidative metabolism [81].
WAT also regulates physiology systemically through secretion of adipokines, such as leptin and adiponectin. Adiponectin combats obesity and diabetes, enhances insulin sensitivity, and promotes proper glucose homeostasis. During exercise, the muscle adiponectin receptor is activated and induces expression of SIRT1, AMPK, and PGC-1α in a Ca2+-dependent manner, which in turn drives fatty acid oxidation and mitochondrial biogenesis [82]. A number of SIRT1 benefits have been reported to occur via WAT. During fasting, SIRT1 can promote fat mobilization from WAT to support lipid oxidation in liver and muscle [83]. Further, SIRT1 can induce white fat to switch into metabolically active brown fat by deacetylating two critical lysine residues on PPARγ (Figure 1) [84]. Conversely, excess energy, which can be induced by a high-fat diet, causes activation of caspase I as a part of the inflammasome, which cleaves SIRT1 in WAT [29]. This reduction in adipose SIRT1 contributes to the metabolic dysfunction induced by this diet. In summary, sirtuins also play critical roles in adapting the physiology of muscle and WAT according to nutrient availability.
Metabolic regulation in vascular endothelium and the heart
Another major age-associated disease is atherosclerosis, which is caused in part by chronic inflammation in blood vessels. With aging, the lack of regeneration capacity together with senescence and cell death strongly compromise the function of blood vessels. Nitric oxide is crucial in maintaining a functioning vascular endothelium. Nitric oxide can promote angiogenesis and smooth muscle proliferation, and reduces the accumulation of atherosclerotic plaques. Moreover, the production of nitric oxide from the endothelial nitric oxide synthase (eNOS) is important for muscle relaxation, lowering of blood pressure, and general endothelium health. Interestingly, SIRT1 and eNOS form a positive regulatory loop: upon CR, eNOS induces SIRT1 expression and SIRT1 further promotes eNOS activity through deacetylation [85].
In the heart, eNOS plays a role in responding to CR by promoting SIRT1 entry into the nucleus, which increases myocardial ischemic tolerance [86]. Additionally, SIRT1 protects against hypertrophy through PPARα activation and increased fat oxidation (Figure 1) [87]. However, high levels of cardiac-specific expression of SIRT1 can be detrimental [88]. It is noteworthy that exogenous NAD+ supplementation via NAD precursors can block hypertrophy by a mechanism that appears to require SIRT3 [89]. Besides SIRT1, other nuclear sirtuins were also demonstrated to be vital in maintaining cardiac health. SIRT6- and SIRT7-deficient mice displayed a cardiac hypertrophy phenotype due to upregulated IGF signaling and p53 activity, respectively [90, 91]. These findings indicate that sirtuins exert beneficial effects on cardiac health by coordinating nuclear and mitochondrial programs.
Metabolic regulation in the hypothalamus
The hypothalamus is an area in the brain important for coordinating systemic mammalian physiology (Figure 2). Diurnal activities, including feeding, body temperature, energy expenditure, and other metabolic functions, are all governed by specific neurons within the hypothalamus. SIRT1 levels in the hypothalamus change in response to diet, and appear to mediate several aspects of hypothalamic control (Figure 2) [92]. For example, the response of the somatotropic axis to CR is blocked in the SIRT1 brain specific knockouts [33]. Further, during CR, SIRT1 levels increase in the dorsomedial hypothalamus (DMH) and lateral hypothalamus (LH), and SIRT1 transgenic overexpression in these neurons promotes higher physical activity and increased body temperature through upregulation of the orexin type 2 receptor, a receptor involved in the central feedback mechanisms that regulate feeding behavior [93]. In the anorexigenic pro-opiomelanocortin (POMC) neurons SIRT1 is essential for maintaining normal energy expenditure. Mice devoid of SIRT1 specifically in POMC neurons are susceptible to diet-induced obesity [94]. SIRT1 in the SF1 (steroidogenic factor 1) neurons is also protective against obesity and diabetes [95]. In addition, SIRT1 can influence feeding by repressing the FOXO1-dependent release of the orexigenic agouti-related peptide [96] and controlling the signaling output in the ventromedial hypothalamic neurons (VMH) [97]. However, pan-neuronal deletion of SIRT1 was surprisingly associated with insulin sensitization in hypothalamic neurons and systemically in peripheral tissues such as liver and muscle [98]. In the suprachiasmatic nucleus (SCN), which mediates circadian control centrally in mammals, SIRT1 can influence the circadian amplitude via upregulation of the core transcription factor, BMAL1, and other components of the clock machinery (Figure 2) [99]. It is important to note that SIRT1 level declines with aging in the SCN and, indeed, overexpressing SIRT1 can delay the age-related decline in central circadian function [99]. Moreover, transgenic overexpression of SIRT1 in the DMH and LH slows aging and extends lifespan in males and females [13]. In conclusion, it is becoming clear that the hypothalamus may be a central regulator of aging and the weight of evidence suggests that hypothalamic SIRT1 plays an important role in this brain region in aging-related function.
Sirtuins and cancer
Numerous experimental results exist that support a relationship between sirtuins and cancer. Significantly, several sirtuins have been reported to have tumor-suppressing activities: SIRT1 overexpression is sufficient to suppress colon cancer growth in the APCmin/+ model [100]. Further, mice heterozygous for SIRT1 and p53 developed spontaneous tumors, indicating that SIRT1 might function as a haplo-insufficient tumor suppressor [101]. However, it should be noted that numerous reports also show that SIRT1 expression can positively correlate with malignancy in certain human cancers [14]. These findings led to the idea that SIRT1 expression may suppress tumor formation, but its expression may actually aid the growth of certain, already established, tumors. SIRT2 regulates cell cycle, and mice deficient for SIRT2 develop mammary tumors in females and hepatocellular carcinoma in males, due to an altered anaphase-promoting complex cyclosome activity [102].