Hepatokines: Linking nonalcoholic fatty liver disease and insulin resistance

Meex, Ruth C. R.; Watt, Matthew J.

doi:10.1038/nrendo.2017.56

Cited by 631Liver Disease Diagnosis and TreatmentAdipokines, Inflammation, and Metabolic DiseasesLiver physiology and pathology

Hepatokines: Linking nonalcoholic fatty liver disease and insulin resistance

Meex, Ruth C. R., Watt, Matthew J.·2017·Nature Reviews Endocrinology

DOI 10.1038/nrendo.2017.56

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Abstract

Hepatic steatosis is an underlying feature of nonalcoholic fatty liver disease (NAFLD), which is the most common form of liver disease and is present in up to ∼70% of individuals who are overweight. NAFLD is also associated with hypertriglyceridaemia and low levels of HDL, glucose intolerance, insulin resistance and type 2 diabetes mellitus. Hepatic steatosis is a strong predictor of the development of insulin resistance and often precedes the onset of other known mediators of insulin resistance. This sequence of events suggests that hepatic steatosis has a causal role in the development of insulin resistance in other tissues, such as skeletal muscle. Hepatokines are proteins that are secreted by hepatocytes, and many hepatokines have been linked to the induction of metabolic dysfunction, including fetuin A, fetuin B, retinol-binding protein 4 (RBP4) and selenoprotein P. In this Review, we describe the factors that influence the development of hepatic steatosis, provide evidence of strong links between hepatic steatosis and insulin resistance in non-hepatic tissues, and discuss recent advances in our understanding of how steatosis alters hepatokine secretion to influence metabolic phenotypes through inter-organ communication.

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The detrimental hepatokines fetuin A and selenoprotein P are increased in insulin-resistant states.
“the detrimental hepatokines fetuin A and selenoprotein P, which are increased in insulin-resistant states [23]”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [23]
The decrease of unfavorable hepatokines and the reversal of hepatic steatosis that frequently accompanies obesity could be achieved with exercise interventions.
“The decrease of such unfavorable hepatokines and the reversal of the hepatic steatosis that frequently accompanies the obese state [3,23] could be achieved with exercise interventions.”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [23]
If the liver's capacity to synthesize and export lipids is overrun by excess substrate, intrahepatic lipid accumulation and steatosis ensue, exacerbating local and systemic insulin resistance.
“if the capacity of the liver to synthesize and export lipids is overrun by excess substrate, intrahepatic lipid accumulation and steatosis eventually ensue, which have been described to exacerbate not only local, but also systemic insulin-resistance [23]”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [23]
Fetuin A and selenoprotein P could blunt the beneficial effects of exercise-inducible factors.
“could blunt the beneficial effects of exercise-inducible factors”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [23]
The antioxidative and anti-inflammatory effects of irisin in hepatocytes may help decrease hepatic steatosis and favor a healthy hepatokine profile that contributes to decreased fat mass.
“the antioxidative and anti-inflammatory effects of irisin have also been described in hepatocytes, which may help decrease hepatic steatosis [65] and favor a healthy hepatokine profile which also contributes to decreased fat mass [23].”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [23]

Excessive levels of selenoprotein P have been shown in humans with metabolic diseases and are positively correlated with insulin resistance, consistent with its insulin-desensitizing effects observed in animal and in vitro models.
“Excessive levels of selenoprotein P (SeP) have been shown in humans with metabolic diseases and are positively correlated with insulin resistance, which is consistent with its insulin-desensitizing effects observed in animal and in vitro models [23].”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [23]
In the long term, reduced WAT depots by exercise favor a shift in the adipokine profile and possibly the hepatokine profile due to the reduction of hepatic steatosis that occurs concomitantly with weight loss.
“In the long term, reduced WAT depots by exercise favor a shift in the adipokine profile [218,219,220] (9a), and possibly the hepatokine profile (9b), due to the reduction of hepatic steatosis that occurs concomitantly with weight loss [23].”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [23]
Impaired hepatic FAO, increased circulating FFAs in the setting of basal VAT lipolysis, and exaggerated lipogenesis are considered pathogenic hallmarks of hepatic steatosis.
“Impaired hepatic FAO (most likely due to mitochondrial dysfunction in hepatocytes), increased circulating FFAs in the setting of basal VAT lipolysis (secondary to full-blown insulin resistance), and exaggerated lipogenesis, are considered pathogenic hallmarks of hepatic steatosis [23].”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [23]
Hepatic steatosis has been shown to perpetuate obesity and the systemic proinflammatory and insulin-resistant state.
“Hepatic steatosis, present in up to 70% of individuals with overweight and in >90% of morbidly obese ones [23], has been shown to perpetuate obesity and the systemic proinflammatory and insulin-resistant state.”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [23]
In mice, overexpression of adropin increases fatty acid oxidation throughout the body.
“On the other hand, it has been seen that in mice, the overexpression of adropin reduces weight gain, attenuates hepatosteatosis, increases fatty acid oxidation throughout the body, improves insulin sensitivity, and improves glucose tolerance [67].”
From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [67]
Intermittent hypoxia generates stress that increases the levels of seleno-protein P in human hepatocytes.
“In addition, studies have shown that intermittent hypoxia generates stress that increases the levels of seleno-protein P in human hepatocytes, increasing insulin resistance, accumulating fat in adipose tissue, and aggravating risks of developing atherosclerosis [67].”
From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [67]
Deletion of LECT2 increases insulin sensitivity in skeletal muscle in rats.
“Therefore, LECT2 can be an important marker to explain how the fatty liver leads to insulin resistance in obesity since its deletion of LECT2 increases insulin sensitivity in skeletal muscle in rats [67].”
From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [67]

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Early Hepatic Insulin Resistance Precedes the Onset of Diabetes in Obese C57BLKS-db/db Mice
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Metabolic Consequences of Hepatic Steatosis in Overweight and Obese Adolescents
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Downstream Signaling Pathways in Mouse Adipose Tissues Following Acute In Vivo Administration of Fibroblast Growth Factor 21
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Polysome Profiling in Liver Identifies Dynamic Regulation of Endoplasmic Reticulum Translatome by Obesity and Fasting
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Alcohol Disrupts Endoplasmic Reticulum Function and Protein Secretion in Hepatocytes
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Sex hormones, sex hormone binding globulin, and abdominal aortic calcification in women and men in the multi-ethnic study of atherosclerosis (MESA)
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Serum FGF21 increases with hepatic fat accumulation in pediatric onset intestinal failure
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Genetic variants in selenoprotein P plasma 1 gene (SEPP1) are associated with fasting insulin and first phase insulin response in Hispanics
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Association Between Serum Fibroblast Growth Factor 21 and Mortality Among Patients With Coronary Artery Disease
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RBP4 functions as a hepatokine in the regulation of glucose metabolism by the circadian clock in mice
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Serum adropin level in patients with stable coronary artery disease
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Abdominal Visceral Fat Reduction Is Associated with Favorable Changes of Serum Retinol Binding Protein-4 in Nondiabetic Subjects
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Angiopoietin-like protein 4 improves glucose tolerance and insulin resistance but induces liver steatosis in high-fat-diet mice
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Increased Mitochondrial Oxidative Phosphorylation in the Liver Is Associated With Obesity and Insulin Resistance
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MTTP-297H polymorphism reduced serum cholesterol but increased risk of non-alcoholic fatty liver disease-a cross-sectional study
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Serum fetuin B level increased in subjects of nonalcoholic fatty liver disease: a case-control study
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Salsalate and Adiponectin Improve Palmitate-Induced Insulin Resistance via Inhibition of Selenoprotein P through the AMPK-FOXO1α Pathway
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Rapid response of the steatosis-sensing hepatokine LECT2 during diet-induced weight cycling in mice
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MRI measurement of liver fat content predicts the metabolic syndrome
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Plasma fetuin-A triggers inflammatory changes in macrophages and adipocytes by acting as an adaptor protein between NEFA and TLR-4
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Low Serum Sex Hormone-Binding Globulin Associated with Insulin Resistance in Men with Nonalcoholic Fatty Liver Disease
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AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease
Rinella, M. E., Neuschwander-Tetri, B. A., Siddiqui, M. S., Abdelmalek, M. F., Caldwell, S., Barb, D., Kleiner, D. E., & Loomba, R. (2023) · Hepatology · doi:10.1097/hep.0000000000000323 · Cited by 2,667 · see citing works
Inflammation in obesity, diabetes, and related disorders
Rohm, T. V., Meier, D. T., Olefsky, J. M., & Donath, M. Y. (2022) · Immunity · doi:10.1016/j.immuni.2021.12.013 · Cited by 2,066 · see citing works
Gut microbial metabolites in obesity, NAFLD and T2DM
Canfora, E. E., Meex, R. C. R., Venema, K., & Blaak, E. E. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0156-z · Cited by 1,493 · see citing works
Self-citation
Western Diet and the Immune System: An Inflammatory Connection
Christ, A., Lauterbach, M., & Latz, E. (2019) · Immunity · doi:10.1016/j.immuni.2019.09.020 · Cited by 907 · see citing works
Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis
Xiong, X., Kuang, H., Ansari, S., Liu, T., Gong, J., Wang, S., Zhao, X.-Y., Ji, Y., Li, C., Guo, L., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.028 · Cited by 784 · see citing works
Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women
Hoyles, L., Fernández-Real, J.-M., Federici, M., Serino, M., Abbott, J., Charpentier, J., Heymes, C., Luque, J. L., Anthony, E., Barton, R. H., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0061-3 · Cited by 720 · see citing works
The Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance
Watt, M. J., Miotto, P. M., De Nardo, W., & Montgomery, M. K. (2019) · Endocrine Reviews · doi:10.1210/er.2019-00034 · Cited by 615 · see citing works
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Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals
Mantovani, A., Petracca, G., Beatrice, G., Tilg, H., Byrne, C. D., & Targher, G. (2021) · Gut · doi:10.1136/gutjnl-2020-322572 · Cited by 481 · see citing works
Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis
Mantovani, A., Petracca, G., Beatrice, G., Csermely, A., Lonardo, A., Schattenberg, J. M., Tilg, H., Byrne, C. D., & Targher, G. (2022) · Gut · doi:10.1136/gutjnl-2020-323082 · Cited by 402 · see citing works
Cytokines and abnormal glucose and lipid metabolism
Shi, J., Fan, J., Su, Q., & Yang, Z. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00703 · Cited by 282 · see citing works
The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review
Gonzalez-Gil, A. M., & Elizondo-Montemayor, L. (2020) · Nutrients · doi:10.3390/nu12061899 · Cited by 278 · see citing works
“On the other hand, the detrimental hepatokines fetuin A and selenoprotein P, which are increased in insulin-resistant states [23], could blunt the beneficial effects of exercise-inducible factors.”
BackgroundInfluential
Inter-organ crosstalk during development and progression of type 2 diabetes mellitus
Xourafa, G., Korbmacher, M., & Roden, M. (2024) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00898-1 · Cited by 274 · see citing works
Mitochondrial dysfunction-related lipid changes occur in nonalcoholic fatty liver disease progression
Peng, K.-Y., Watt, M. J., Rensen, S., Greve, J. W., Huynh, K., Jayawardana, K. S., Meikle, P. J., & Meex, R. C. R. (2018) · Journal of Lipid Research · doi:10.1194/jlr.m085613 · Cited by 220 · see citing works
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Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions
de Oliveira dos Santos, A. R., de Oliveira Zanuso, B., Miola, V. F. B., Barbalho, S. M., Santos Bueno, P. C., Flato, U. A. P., Detregiachi, C. R. P., Buchaim, D. V., Buchaim, R. L., Tofano, R. J., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052639 · Cited by 189 · see citing works
Inter‐organ communication: a gatekeeper for metabolic health
Castillo‐Armengol, J., Fajas, L., & Lopez‐Mejia, I. C. (2019) · The EMBO Reports · doi:10.15252/embr.201947903 · Cited by 178 · see citing works
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Authors: Meex, R. C. R., & Watt, M. J.
Affiliations: Maastricht University (NL)
Monash University (AU)
Corresponding author: Meex, Ruth C. R.
Watt, Matthew J.
ORCID: Meex, Ruth C. R.
Watt, Matthew J.
Venue: Nature Reviews Endocrinology
Publisher: Springer Science and Business Media LLC
Published: 2017-06-09
Volume: 13
Issue: 9
Pages: 509-520
ISSN: 1759-5029 (ISSN-L)
1759-5037
DOI: 10.1038/nrendo.2017.56
OpenAlex: W2624389654
Cited by: 631
References: 197
Citations by year: 2026: 38 · 2025: 63 · 2024: 69 · 2023: 93 · 2022: 79 · 2021: 94 · 2020: 68 · 2019: 66 · 2018: 49 · 2017: 12
FWCI: 7.06
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Reviews Endocrinology (publishedVersion)
PubMed (publishedVersion)
Research Publications (Maastricht University) (submittedVersion)
Funders: National Health and Medical Research Council
National Medical Research Council
Topics: Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords: hepatokines, non-alcoholic fatty liver disease, insulin resistance, hepatic steatosis, fetuin-A, fetuin-B, retinol-binding protein 4, selenoprotein P, glucose metabolism, type 2 diabetes, inter-organ communication, hypertriglyceridemia, HDL cholesterol
MeSH terms: Animals, Blood Proteins, Diabetes Mellitus, Type 2, Humans, Insulin Resistance, Liver, Obesity, Hypertriglyceridemia, Overweight, Lipid Metabolism, Selenoprotein P, Retinol-Binding Proteins, Plasma, Diet, High-Fat, alpha-2-HS-Glycoprotein, Fetuin-B, Non-alcoholic Fatty Liver Disease

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Hepatokines: Linking nonalcoholic fatty liver disease and insulin resistance

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