PPP2R5C couples hepatic glucose and lipid homeostasis
Open accessAbstract
In mammals, the liver plays a central role in maintaining carbohydrate and lipid homeostasis by acting both as a major source and a major sink of glucose and lipids. In particular, when dietary carbohydrates are in excess, the liver converts them to lipids via de novo lipogenesis. The molecular checkpoints regulating the balance between carbohydrate and lipid homeostasis, however, are not fully understood. Here we identify PPP2R5C, a regulatory subunit of PP2A, as a novel modulator of liver metabolism in postprandial physiology. Inactivation of PPP2R5C in isolated hepatocytes leads to increased glucose uptake and increased de novo lipogenesis. These phenotypes are reiterated in vivo, where hepatocyte specific PPP2R5C knockdown yields mice with improved systemic glucose tolerance and insulin sensitivity, but elevated circulating triglyceride levels. We show that modulation of PPP2R5C levels leads to alterations in AMPK and SREBP-1 activity. We find that hepatic levels of PPP2R5C are elevated in human diabetic patients, and correlate with obesity and insulin resistance in these subjects. In sum, our data suggest that hepatic PPP2R5C represents an important factor in the functional wiring of energy metabolism and the maintenance of a metabolically healthy state.
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Hepatocyte-specific B56γ knockdown reduced B56γ mRNA by 85% and protein by 50% in the liver.
“These mice showed a significant reduction in B56γ mRNA (85%) and protein (50%) levels in the liver.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [73]
This phenotype was not caused by effects on gluconeogenesis or insulin-induced AKT or GSK-3β phosphorylation, but rather by increased glucose uptake by hepatocytes.
“this phenotype was not caused by any effects on gluconeogenesis or insulin-induced AKT or GSK-3β phosphorylation, but rather by increased glucose uptake by the hepatocytes.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [73]
B56γ knockdown livers had increased triglyceride levels, suggesting increased de novo lipogenesis.
“increased triglyceride levels were found in the B56γ KD livers, suggestive for increased de novo lipogenesis.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [73]
BIO-ID and PLA assays revealed a role for PP2A-B56γ in directly controlling AMPK activity, with enhanced Thr172 phosphorylation in B56γ knockdown livers, and in suppressing HIF1α transcriptional activity.
“BIO-ID and PLA assays revealed a role for PP2A-B56γ in the direct control of AMP-activated protein Kinase (AMPK) activity (Thr172 phosphorylation was enhanced in the B56γ KD livers) and in the suppression of Hypoxia Inducible Factor 1α (HIF1α) transcriptional activity.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [73]
In livers of type 2 diabetic patients, PPP2R5C expression was significantly increased, and visceral obesity correlated with PPP2R5C transcription in non-diabetic patients.
“in livers of type 2 diabetic patients, PPP2R5C expression was significantly increased, and visceral obesity correlated with PPP2R5C transcription in non-diabetic patients [73].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [73]
B56γ knockdown increased insulin sensitivity and glucose tolerance without affecting body weight, similar to liver-specific Cα knockout mice.
“Although no effects on body weight could be detected, an increased insulin sensitivity and glucose tolerance phenotype was observed, very similar to the liver-specific Cα KO mice.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [73]
Enhanced liver mass, elevated VLDL secretion, and decreased glycogen breakdown upon fasting infer a more detrimental effect on lipid metabolism than on carbohydrate metabolism.
“Together with an enhanced liver mass, elevated VLDL secretion in blood and decreased glycogen breakdown upon fasting, these phenotypes infer a more detrimental effect on lipid metabolism than on carbohydrate metabolism.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [73]
An indirect role for PP2A-B56γ was inferred in suppressing SREBP-1-regulated transcription.
“an indirect role for PP2A-B56γ was inferred in suppressing Sterol Regulatory Element Binding Protein 1 (SREBP-1)-regulated transcription [73].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [73]
In diabetic db/db mice, liver-specific Ppp2r5c knockdown worsened dyslipidemia while considerably improving glucose metabolism.
“in diabetic db/db mice, where liver-specific Ppp2r5c knockdown worsened their dyslipidemia, while their glucose metabolism was considerably improved.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [73]
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- Authors
- Cheng, Y.-S., Seibert, O., Klöting, N., Dietrich, A., Straßburger, K., Fernández-Veledo, S., Vendrell, J. J., Zorzano, A., Blüher, M., Herzig, S., Berriel Diaz, M., & Teleman, A. A.
- Affiliations
- German Cancer Research Center (DE)
- Leipzig University (DE)
- Institut de Recerca Biomèdica Catalunya Sud (ES)
- Corresponding author
- Teleman, Aurelio A.
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-10-06
- Volume
- 11
- Issue
- 10
- Pages
- e1005561
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC4595073
- OpenAlex
- W2259447096
- Cited by
- 43
- References
- 53
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 4 · 2022: 4 · 2021: 1 · 2020: 5 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 9
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (publishedVersion, cc-by)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, other-oa)
- Rovira & Virgili repository (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Site cant be reached (submittedVersion, cc-by)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
- Funders
- Deutsches Krebsforschungszentrum
- Deutsche Forschungsgemeinschaft (SFB1118)
- Ministerio de Economía y Competitividad (SAF2012, SAF2012-36186)
- Fritz Thyssen Stiftung
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CP10/00438, CB07708/0012)
- Instituto de Salud Carlos III (CP10/ 00438, CB07708/0012)
- European Regional Development Fund (SAF2012-36186, CP10/00438, CB07708/0012)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- PPP2R5C, PP2A regulatory subunit, hepatic glucose homeostasis, hepatic lipid homeostasis, de novo lipogenesis, glucose uptake, postprandial metabolism, glucose tolerance, insulin sensitivity, triglycerides, AMPK, SREBP1, insulin resistance, obesity, diabetes mellitus, hepatocytes
- MeSH terms
- Animals, Dietary Carbohydrates, Energy Metabolism, Glucose, Humans, Insulin Resistance, Liver, Obesity, Hepatocytes, Lipogenesis, Lipid Metabolism, Mice, Sterol Regulatory Element Binding Protein 1, Protein Phosphatase 2, AMP-Activated Protein Kinases
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