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Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARα and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States
Open accessAbstract
Mice fed a high-fat, low-carbohydrate ketogenic diet (KD) exhibit marked changes in hepatic metabolism and energy homeostasis. Here, we identify liver-derived fibroblast growth factor 21 (FGF21) as an endocrine regulator of the ketotic state. Hepatic expression and circulating levels of FGF21 are induced by both KD and fasting, are rapidly suppressed by refeeding, and are in large part downstream of PPARalpha. Importantly, adenoviral knockdown of hepatic FGF21 in KD-fed mice causes fatty liver, lipemia, and reduced serum ketones, due at least in part to altered expression of key genes governing lipid and ketone metabolism. Hence, induction of FGF21 in liver is required for the normal activation of hepatic lipid oxidation, triglyceride clearance, and ketogenesis induced by KD. These findings identify hepatic FGF21 as a critical regulator of lipid homeostasis and identify a physiological role for this hepatic hormone.
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In the citing paper
“In the liver, FGF21 upregulates β-oxidation [160] and downregulates lipogenesis [167].”
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 [160]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“For instance, BAIBA [104] and FGF21 [160] have been shown to increase hepatic β-oxidation (6)”
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 [160]
Experimental — accuracy not yet measuredIn the citing paper
“The metabolic regulator FGF21 is expressed and released into the general circulation by several tissues such as the liver, WAT, BAT, and the heart.7, 8, 9, 10, 11”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [7]
In the citing paper
“Interestingly, mice that overexpress FGF-21, a circulating FGF which is induced by a ketogenic diet 106, are lean and have increased brown fat 107, suggesting that the beneficial metabolic effects induced by a ketogenic diet are brought about in part by increases in BAT mass.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [106]
In the citing paper
“FGF21 was initially proposed to be a late-fasting/starvation factor, because it is transcriptionally induced during extended fasting, through a mechanism dependent on the transcription factor PPARα, and it regulates the adaptive fasting response20,21.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [21]
In the citing paper
“Classically recognized as a fasting hormone regulated by the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) [150,151]”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [150]
In the citing paper
“FGF21 is markedly induced by ketogenic diets in rodents and has been proposed to be a key mediator of hepatic lipid metabolism during ketotic states (6, 7).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [7]
In the citing paper
“Knockdown of hepatic Fgf21 using adenovirus-mediated expression of short hairpin RNAs directed against Fgf21 mRNA resulted in significantly elevated hepatic triglyceride and plasma lipid levels, and impaired ketosis (7).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [7]
In the citing paper
“Multiple groups discovered that PPARα-mediated induction of FGF21 is important for the adaptive fasting response (7, 54).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [7]
In the citing paper
“Fibroblast growth factor 21 (FGF21) was first identified as an hepatokine 61 and has been shown to be necessary for the adaptation to fasting 62, 63.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [62]
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Metadata
- Authors
- Badman, M. K., Pissios, P., Kennedy, A. R., Koukos, G., Flier, J. S., & Maratos-Flier, E.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- ORCID
- Flier, Jeffrey S.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2007-06
- Volume
- 5
- Issue
- 6
- Pages
- 426-437
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2131622156
- Cited by
- 1,495
- References
- 29
- Citations by year
- 2026: 40 · 2025: 65 · 2024: 67 · 2023: 81 · 2022: 93 · 2021: 97 · 2020: 83 · 2019: 100 · 2018: 106 · 2017: 105 · 2016: 112 · 2015: 93 · 2014: 92 · 2013: 81 · 2012: 79
- FWCI
- 19.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01dk069983-05)
- National Heart, Lung, and Blood Institute (HL48739, R01HL048739)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK056116, P30DK046200, R01-DK-069983, 5P30DK46200-14)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology (medical) › Diet and metabolism studies
- Keywords
- FGF21, PPARα, ketogenic diet, hepatic lipid metabolism, ketogenesis, hepatic lipid oxidation, triglyceride clearance, fasting, refeeding, hepatic steatosis, serum ketones, hepatic hormones, energy homeostasis
- MeSH terms
- Adenoviridae, Animals, Hypolipidemic Agents, Cells, Cultured, Fibroblast Growth Factors, Gene Expression Regulation, Ketosis, Liver, Male, Mice, Inbred C57BL, Fenofibrate, RNA, Messenger, Transfection, Immunoblotting, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Hepatocytes, PPAR alpha, Lipid Metabolism, Mice
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