A novel hepatokine, HFREP1, plays a crucial role in the development of insulin resistance and type 2 diabetes
Open accessAbstract
Aims/hypothesis Type 2 diabetes is highly correlated with nonalcoholic fatty liver disease (NAFLD). Hepatocyte-derived fibrinogen-related protein 1 (HFREP1) is a hepatokine that mediates NAFLD development; however, the role of HFREP1 in the development of insulin resistance and diabetes remains obscure.Methods A total of 193 age- and sex-matched participants with normal glucose tolerance, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and newly diagnosed diabetes (NDD) were recruited for a cross-sectional study. Plasma HFREP1 levels were measured and multivariate linear regression analysis was used to evaluate the relationship between HFREP1, IFG, IGT and NDD. The causal relationship between HFREP1 and insulin resistance was then investigated in animal and cell models. Glucose and insulin tolerance tests, and euglycaemic-hyperinsulinaemic clamp, were used to evaluate insulin sensitivity in animals with Hfrep1 overexpression or knockdown in liver by lentiviral vectors. HepG2 cells were used to clarify the possible mechanism of HFREP1-induced insulin resistance.Results Plasma HFREP1 concentrations were significantly increased in participants with IFG, IGT and NDD. HFREP1 concentrations were independently associated with fasting plasma glucose levels, insulin resistance, IFG, IGT and NDD. Injection of recombinant HFREP1 or Hfrep1 overexpression induced insulin resistance in mice, and HFREP1 disrupted insulin signalling to induce insulin resistance through an extracellular signal-regulated kinase (ERK)1/2-dependent pathway. Moreover, hepatic knockdown of HFREP1 improved insulin resistance in both mice fed a high-fat diet and ob/ob mice.Conclusions/interpretation These findings highlight the crucial role of HFREP1 in insulin resistance and diabetes, and provide a potential strategy and biomarker for developing therapeutic approaches to combat these diseases.
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In humans, serum levels of hepassocin are elevated in pre-diabetes, DM2, and NAFLD.
“However, it has been shown that in humans, serum levels of hepassocin are elevated in pre-diabetes, DM2, and NAFLD because of their association with impaired fasting glucose, glucose intolerance, and insulin resistance [77].”
From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [77]
Hepassocin is a hepatokine involved in the development of insulin resistance and obesity.
“Hepassocin (also called fibrinogen-like protein 1 and hepatocyte-derived fibrinogen-related protein 1, HFREP1) is a hepatokine involved in the development of insulin resistance and obesity [217].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [217]
Hepassocin increases phosphorylation of ERK1/2, leading to hepatic lipogenesis and development of hepatic steatosis.
“Hepassocin increases the phosphorylation of ERK1/2, leading to hepatic lipogenesis and the development of hepatic steatosis [217,218].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [217]
Plasma levels of hepassocin are associated with fasted plasma glucose, HOMA-IR, and prediabetes and increase in patients with type 2 diabetes.
“Plasma levels of hepassocin are associated with fasted plasma glucose, HOMA-IR, and prediabetes and increase in patients with type 2 diabetes (Table 1) [217,220].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [217]
Hepatic expression of hepassocin increases in mice with high-fat diet-induced NAFLD.
“Several studies demonstrated that hepatic expression of hepassocin increased in mice with high-fat diet-induced NAFLD [217,220,221].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [217]
Administration of recombinant hepassocin or hepatic overexpression of hepassocin in mice induces insulin resistance in liver and skeletal muscle, while loss of hepassocin improves high-fat diet-induced insulin resistance in wild-type and ob/ob mice.
“Administration of recombinant hepassocin or hepatic overexpression of hepassocin in mice induces insulin resistance in the liver and skeletal muscle, while loss of hepassocin improves high-fat diet-induced insulin resistance in wild-type and ob/ob mice [217] (Figure 3).”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [217]
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- Authors
- Wu, H.-T., Ou, H.-Y., Hung, H.-C., Su, Y.-C., Lu, F.-H., Wu, J.-S., Yang, Y.-C., Wu, C.-L., & Chang, C.-J.
- Affiliations
- National Cheng Kung University Hospital (TW)
- National Cheng Kung University (TW)
- Corresponding author
- Wu, Chao-Liang
- Chang, Chih-Jen
- ORCID
- Venue
- Diabetologia
- Published
- 2016-05-25
- Volume
- 59
- Issue
- 8
- Pages
- 1732-1742
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2403136861
- Cited by
- 96
- References
- 26
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 9 · 2023: 14 · 2022: 13 · 2021: 15 · 2020: 7 · 2019: 11 · 2018: 4 · 2017: 5
- FWCI
- 6.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- the Ministry of Science and Technology of Republic of China (103-2314-B-006-027-MY2)
- Ministry of Science and Technology of Republic of China (103-2314-B-006-065)
- National Cheng Kung University Hospital (NCKUH-10306023)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- hepatokines, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, impaired fasting glucose, impaired glucose tolerance, newly diagnosed diabetes, insulin signaling, MAPK/ERK pathway, hepatic insulin sensitivity, biomarkers
- MeSH terms
- Aged, Animals, Blood Glucose, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Fibrinogen, Humans, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Middle Aged, Neoplasm Proteins, Glucose Intolerance, Mice, Hep G2 Cells
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