Newly discovered endocrine functions of the liver

Abstract

The liver, the largest solid visceral organ of the body, has numerous endocrine functions, such as direct hormone and hepatokine production, hormone metabolism, synthesis of binding proteins, and processing and redistribution of metabolic fuels. In the last 10 years, many new endocrine functions of the liver have been discovered. Advances in the classical endocrine functions include delineation of mechanisms of liver production of endocrine hormones [including 25-hydroxyvitamin D, insulin-like growth factor 1 (IGF-1), and angiotensinogen], hepatic metabolism of hormones (including thyroid hormones, glucagon-like peptide-1, and steroid hormones), and actions of specific binding proteins to glucocorticoids, sex steroids, and thyroid hormones. These studies have furthered insight into cirrhosis-associated endocrinopathies, such as hypogonadism, osteoporosis, IGF-1 deficiency, vitamin D deficiency, alterations in glucose and lipid homeostasis, and controversially relative adrenal insufficiency. Several novel endocrine functions of the liver have also been unraveled, elucidating the liver's key negative feedback regulatory role in the pancreatic α cell-liver axis, which regulates pancreatic α cell mass, glucagon secretion, and circulating amino acid levels. Betatrophin and other hepatokines, such as fetuin-A and fibroblast growth factor 21, have also been discovered to play important endocrine roles in modulating insulin sensitivity, lipid metabolism, and body weight. It is expected that more endocrine functions of the liver will be revealed in the near future.

Keywords: Amino acids; Endocrine function; Fibroblast growth factor 21; Hepatokine; Hormone; Liver.

Figure 1

Schematic drawing of regulation of pancreatic α cell number and glucagon secretion by amino acid levels controlled by the liver. The numbers indicate specific ways to disrupt glucagon signaling. (1) Glucagon deletion; (2) Prohormone convertase 2 deletion (with no mature glucagon secretion); (3) Glucagon receptor (GCGR) global deletion; (4) GCGR liver-specific deletion; (5) GCGR inactivating mutation; (6) GCGR antisense RNA; (7) GCGR antagonists; (8) GCGR antibodies; and (9) Gsα liver-specific deletion. See text for details. Citation: Yu R, Zheng Y, Lucas MB, Tong YG. Elusive liver factor that causes pancreatic α cell hyperplasia: A review of literature. World J Gastrointest Pathophysiol 2015; 6(4): 131-139. Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc[67]. GCGR: Glucagon receptor.

Figure 2

Major classic and novel endocrine functions of the liver. Left, major classic endocrine functions of the liver; right, novel endocrine functions of the liver. See text for details. IGF-1: Insulin-like growth factor 1; TBG: Thyroxine binding globulin; CBG: Cortisol binding globulin; SHBG: Sex hormone binding globulin.