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The Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance
Open accessAbstract
The liver is a dynamic organ that plays critical roles in many physiological processes, including the regulation of systemic glucose and lipid metabolism. Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. Through the use of advanced mass spectrometry “omics” approaches and detailed experimentation in cells, mice, and humans, we now understand that the liver secretes a wide array of proteins, metabolites, and noncoding RNAs (miRNAs) and that many of these secreted factors exert powerful effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the rapidly evolving field of “hepatokine” biology with a particular focus on delineating previously unappreciated communication between the liver and other tissues in the body. We describe the NAFLD-induced changes in secretion of liver proteins, lipids, other metabolites, and miRNAs, and how these molecules alter metabolism in liver, muscle, adipose tissue, and pancreas to induce insulin resistance. We also synthesize the limited information that indicates that extracellular vesicles, and in particular exosomes, may be an important mechanism for intertissue communication in normal physiology and in promoting metabolic dysregulation in NAFLD.
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“with ~2,500 liver-secreted proteins identified using modern liquid chromatography and mass spectroscopy technologies39.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [39]
In the citing paper
“These exerkines affect glucose and/or lipid metabolism (for example, angiopoietin-like protein 4 in humans and animal models39,79), browning of WAT (FGF21 in a mouse model106), lipolysis (FGF21 in humans and a mouse model77) and the maintenance of cellular homeostasis (heat shock protein 72 in humans107).”
From Exerkines in health, resilience and disease (2022) · cites this paper as [39]
In the citing paper
“fetuin-A worsens peripheral insulin resistance by reducing insulin signalling and glucose transporter type 4 trafficking39.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [39]
In the citing paper
“Activin-E is elevated in the livers and serum of humans with obesity and NAFLD (Table 1) [29]”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [29]
In the citing paper
“Furthermore, knockdown of FST in mice improved insulin sensitivity [29,196].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [29]
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“Hepassocin has also been implicated in skeletal muscle insulin resistance through an AMPK-dependent mechanism [29] (Figure 3).”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [29]
In the citing paper
“These findings coincide with studies in mice that demonstrate increased hepatic expression of SeP in response to high-fat diet feeding, NAFLD, and type 2 diabetes [29,260,265].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [29]
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Common pathogenetic mechanisms of non-alcoholic fatty liver disease and polycystic ovary syndrome
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Mup3 ameliorates the dysregulation of glucose and lipid metabolism in MAFLD.
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MASLD: Lipotoxicity and Imaging Parallels from Liver Steatosis to Kidney Injury
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Metadata
- Authors
- Watt, M. J., Miotto, P. M., De Nardo, W., & Montgomery, M. K.
- Affiliations
- The University of Melbourne (AU)
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
- Corresponding author
- Watt, Matthew J
- Venue
- Endocrine Reviews
- Publisher
- The Endocrine Society
- Published
- 2019-04-25
- Volume
- 40
- Issue
- 5
- Pages
- 1367-1393
- ISSN
- 0163-769X (ISSN-L)
- 1945-7189
- OpenAlex
- W2942227779
- Cited by
- 615
- References
- 385
- Citations by year
- 2026: 61 · 2025: 98 · 2024: 109 · 2023: 98 · 2022: 128 · 2021: 83 · 2020: 31 · 2019: 7
- FWCI
- 9.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrine Reviews (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Health and Medical Research Council (APP1077703, APP1143224, APP1162511, APP1156508)
- Natural Sciences and Engineering Research Council of Canada
- Melbourne Research Scholarship, University of Melbourne (AU)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- non-alcoholic fatty liver disease, insulin resistance, hepatokines, hepatic lipid metabolism, microRNA, extracellular vesicles, exosomes, type 2 diabetes, muscle metabolism, adipose tissue, pancreas
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Endocrine Glands, Humans, Insulin Resistance, Liver, Dyslipidemias, Lipid Metabolism, Non-alcoholic Fatty Liver Disease
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