**Acknowledgements**

hepatosteatosis following high-fat diet feeding [59]. Several glucagon receptor antagonists (GRA) have been developed to reduce hepatic glucose overproduction and improve the overall glycemic status. However, some GRAs including MK-0893 have been shown to dosedependently increase LDL in T2DM patients. In the rodent preclinical trial, blockade of glucagon receptor using various GRAs elevates plasma LDL-c and total cholesterol. This is caused by increased cholesterol absorption instead of the change in cholesterol synthesis or secretion [60]. Taken together, these results suggest that glucagon plays a hypolipidemic effect through its glucagon receptors, making it an interesting and attractive pharmaceutical agent for the

Irisin is a newly identified hormone encoded by the gene fibronectin type III domain-containing protein 5 (FNDC5). It is secreted into the circulation as a cleaved protein product and induced by exercise [61]. Irisin is proposed to mediate the metabolic benefits of exercising by promoting the browning of subcutaneous adipose tissue, reducing visceral obesity and improving glucose and cholesterol metabolism. Circulating the irisin level is negatively associated with fat mass, fasting glucose and dyslipidemia, as well as intrahepatic TG contents in humans [62, 63]. A higher baseline irisin level is associated with the metabolic benefits of diet-restricted treatment on human weight loss [64]. Lentivirus-mediated FNDC5 overexpression or subcutaneous perfusion of irisin promotes lipolysis and reduces hyperlipidemia in obese mice [65]. Irisin is negatively associated with HDL cholesterol and large HDL particles in adults with higher cardiovascular risk [66]. In addition, the serum irisin level is significantly higher in the NAFLD patients than in normal subjects [67]. Elevation of saliva irisin is positively related to total cholesterol [68]. Subcutaneous infusion of irisin decreases body weight, plasma total, VLDL, LDL, HDL cholesterol in diet-induced obese mice. The hepatic levels of total and esterified cholesterol are also reduced. These alterations are associated with significant reduction in the expression of the genes important for cholesterol synthesis, including *Srebp2*, HMG-CoA reductase (*Hmgcr*), the liver X receptor α (*Lxrα*, *Nr1h3*) and HMG CoA synthase (*Hmgcs*) in the liver and primary hepatocytes. Further experiments demonstrate that irisin inhibits cholesterol synthesis in hepatocytes through the activation of AMPK and SREBP2 [69]. As a novel hormone, evidence supporting the critical role of irisin in the regulation of cholesterol or lipid metabolism is still limited. More studies are needed to clarify the role of FNDC5/irisin in the lipid homeostasis under physiological and pathologi-

Cholesterol balance is regulated at multiple steps, including the biosynthesis, uptake, intracellular transport and conversion to bile acids for excretion. Hormones affect cholesterol biosynthesis and uptake by altering the transcription of genes critical for these biological processes (**Table 1**). Novel identified hormones are constantly added into the list implicated

treatment of dyslipidemia and obesity.

26 Cholesterol - Good, Bad and the Heart

**6. Irisin**

cal conditions.

**7. Conclusion**

This work was supported by the National Natural Science Foundation of China (81500619), Natural Science Foundation of Guangdong Province (2016A030310040), Shenzhen Science and Technology Project (JCYJ20160422091658982, JCYJ20150324140036854), Shenzhen Peacock Plan (KQTD20140630100746562,827–000107) and Natural Science Foundation of SZU (201567).
