Hepatokines and metabolism: Deciphering communication from the liver

Abstract

Background: The liver is a key regulator of systemic energy homeostasis and can sense and respond to nutrient excess and deficiency through crosstalk with multiple tissues. Regulation of systemic energy homeostasis by the liver is mediated in part through regulation of glucose and lipid metabolism. Dysregulation of either process may result in metabolic dysfunction and contribute to the development of insulin resistance or fatty liver disease.

Scope of review: The liver has recently been recognized as an endocrine organ that secretes hepatokines, which are liver-derived factors that can signal to and communicate with distant tissues. Dysregulation of liver-centered inter-organ pathways may contribute to improper regulation of energy homeostasis and ultimately metabolic dysfunction. Deciphering the mechanisms that regulate hepatokine expression and communication with distant tissues is essential for understanding inter-organ communication and for the development of therapeutic strategies to treat metabolic dysfunction.

Major conclusions: In this review, we discuss liver-centric regulation of energy homeostasis through hepatokine secretion. We highlight key hepatokines and their roles in metabolic control, examine the molecular mechanisms of each hepatokine, and discuss their potential as therapeutic targets for metabolic disease. We also discuss important areas of future studies that may contribute to understanding hepatokine signaling under healthy and pathophysiological conditions.

Keywords: Glucose homeostasis; Hepatokine; Insulin sensitivity; Liver; Nutrient; Obesity.

Figure 1

Hepatic production of secreted factors controls nutrient and energy homeostasis. The liver plays a central role in regulating systemic energy balance by sensing nutrient availability and altering metabolite and energy production used by various organ systems. The liver communicates with these tissues in part through the production of hepatokines, which are responsible for transmitting information regarding the metabolic status of the liver to target organs, including the CNS, adipose tissues, and muscle. This information is communicated back to the liver in a feedforward loop through hepatokines and other secreted factors, including those produced by the pancreas, to maintain energy balance in response to constant changes in nutrient status. CNS, central nervous system; GDF15, growth differentiation factor 15; FGF21, fibroblast growth factor 21; TSK, Tsukushi; FST, follistatin; ANGPTL, angiopoietin-like; LCN13, lipocalin 13; SMOC1, SPARC-related modular calcium-binding protein-1; IGF1, insulin-like growth factor 1; LECT2, leukocyte cell-derived chemotaxin 2.

Figure 2

Mechanism for physiological effects of hepatokines in target tissues. Hepatokines elicit diverse effects on target tissues. Some hepatokines signal the CNS to regulate body weight homeostasis and nutrient intake, while others act on adipose tissues and muscle to regulate lipid and glucose homeostasis. GDF15, growth differentiation factor 15; FGF21, fibroblast growth factor 21; FST, follistatin; LCN13, lipocalin 13; TSK, Tsukushi; IGF1, insulin-like growth factor 1; UCP1, uncoupling protein 1; SMOC1, SPARC-related modular calcium-binding protein-1; ANGPTL6, angiopoietin-like 6; AMPK, 5′ adenosine monophosphate-activated protein kinase.

Figure 3

Regulation of hepatokine function during obesity and diabetes. Signaling of certain hepatokines to target tissues including skeletal muscle and adipose tissues may result in impaired lipid and glucose homeostasis, ultimately leading to metabolic dysregulation. Some hepatokines increase in the circulation under inflammation conditions, which may result in endocrine-signaling resistance. ANGPTL3, 8, 4, angiopoietin-like 3, 8, 4; LPL, lipoprotein lipase; FFA, free fatty acid; FST, follistatin; LECT2, leukocyte cell-derived chemotaxin 2; HFREP1, hepassocin; IL1β, interleukin-1 beta; TNF-α, tumor necrosis factor alpha; IL6, interleukin-6; AMPK, 5′ adenosine monophosphate-activated protein kinase; FGF21, fibroblast growth factor 21; SMOC1, SPARC-related modular calcium-binding protein-1; ANGPTL6, angiopoietin-like 6.