Loss of hepatic miR-33 improves metabolic homeostasis and liver function without altering body weight or atherosclerosis
Open accessAbstract
Significance: Prior work has suggested that the ability of miR-33, a microRNA involved in regulation of lipid metabolism, to regulate liver function underlies its effects on obesity and/or atherosclerosis. In this work, we selectively remove miR-33 from the liver and demonstrate that, unlike mice globally deficient for miR-33, mice lacking miR-33 in the liver are not predisposed to diet-induced obesity and are actually protected from hepatic insulin resistance and fibrosis. While loss of liver miR-33 increases circulating high-density lipoprotein and increases reverse cholesterol transport in mice on a chow diet, it is not sufficient to decrease atherosclerotic plaque burden under hyperlipidemic conditions where hepatic miR-33 is already repressed. This information will help improve efforts to develop novel therapies against cardiometabolic diseases.
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miR-33 contributes to hepatic lipid accumulation by repressing fatty acid oxidation genes and promoting lipogenesis.
“MiR-33 contributes to hepatic lipid accumulation by repressing fatty acid oxidation genes and promoting lipogenesis.”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [36]
Hepatic deletion of miR-33a reduces liver lipid content by suppressing lipid synthesis and enhancing fatty acid oxidation, improves mitochondrial function, and alleviates oxidative stress through AMPKα and PGC1α activation, leading to reduced activation of the YAP/TAZ pathway.
“Hepatic deletion of miR-33a reduces liver lipid content by suppressing lipid synthesis and enhancing fatty acid oxidation, improves the mitochondrial function, and alleviates oxidative stress through AMPKα and PGC1α activation, leading to reduced activation of the YAP/TAZ pathway.”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [36]
miR-33a knockout in hepatocytes reduces steatosis with improved insulin sensitivity and glucose homeostasis and suppresses the subsequent progression to MASH and hepatocellular carcinoma (HCC) by reducing the lipid burden in the liver.
“MiR-33a knockout in hepatocytes reduces steatosis with improved insulin sensitivity and glucose homeostasis and suppresses the subsequent progression to MASH and hepatocellular carcinoma (HCC) by reducing the lipid burden in the liver 36 , 37) .”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [36]
Cites
MicroRNA-33 and the SREBP Host Genes Cooperate to Control Cholesterol Homeostasis
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miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling
Dávalos, A., Goedeke, L., Smibert, P., Ramírez, C. M., Warrier, N. P., Andreo, U., Cirera-Salinas, D., Rayner, K., Suresh, U., Pastor-Pareja, J. C., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102281108 · Cited by 670 · see citing works
Self-citationOuimet, M., Ediriweera, H. N., Gundra, U. M., Sheedy, F. J., Ramkhelawon, B., Hutchison, S. B., Rinehold, K., van Solingen, C., Fullerton, M. D., Cecchini, K., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci81676 · Cited by 394 · see citing works
Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation*
Gerin, I., Clerbaux, L.-A., Haumont, O., Lanthier, N., Das, A. K., Burant, C. F., Leclercq, I. A., MacDougald, O. A., & Bommer, G. T. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.152090 · Cited by 382 · see citing works
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ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors
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“Fat tolerance test was performed as previously described (32).”
MethodMicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice
Horie, T., Nishino, T., Baba, O., Kuwabara, Y., Nakao, T., Nishiga, M., Usami, S., Izuhara, M., Sowa, N., Yahagi, N., et al. (2013) · Nature Communications · doi:10.1038/ncomms3883 · Cited by 230 · see citing works
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Self-citationPrice, N. L., Singh, A. K., Rotllan, N., Goedeke, L., Wing, A., Canfrán-Duque, A., Diaz-Ruiz, A., Araldi, E., Baldán, Á., Camporez, J.-P., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.074 · Cited by 110 · see citing works
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High-density lipoprotein revisited: biological functions and clinical relevance
von Eckardstein, A., Nordestgaard, B. G., Remaley, A. T., & Catapano, A. L. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehac605 · Cited by 401 · see citing works
microRNA-33 controls hunger signaling in hypothalamic AgRP neurons
Price, N. L., Fernández-Tussy, P., Varela, L., Cardelo, M. P., Shanabrough, M., Aryal, B., de Cabo, R., Suárez, Y., Horvath, T. L., & Fernández-Hernando, C. (2024) · Nature Communications · doi:10.1038/s41467-024-46427-0 · Cited by 25 · see citing works
“…loss of miR-33 in peripheral organs, such as the liver and adipose tissue, that indirectly regulate feeding behavior, did not lead to increased body weight 14 , we nextsoughttodetermineifmiR-33isdirectlyinvolvedinregulatingthe activityoftheAgRPandPOMCneuronsthatpromotesignalsofhunger and satiety.”
BackgroundMethodInfluentialSelf-citationHorie, T., Baba, O., Nishino, T., Yamashita, Y., Tsujisaka, Y., & Ono, K. (2026) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.rv22045 · Cited by 5 · see citing works
- Authors
- Price, N. L., Zhang, X., Fernández-Tussy, P., Singh, A. K., Burnap, S. A., Rotllan, N., Goedeke, L., Sun, J., Canfrán-Duque, A., Aryal, B., Mayr, M., Suárez, Y., & Fernández-Hernando, C.
- Affiliations
- Yale University (US)
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520;
- King's College London (GB)
- Corresponding author
- Price, Nathan L.
- Zhang, Xinbo
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2021-01-25
- Volume
- 118
- Issue
- 5
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7865172
- OpenAlex
- W3124019434
- Cited by
- 50
- References
- 12
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 10 · 2023: 9 · 2022: 8 · 2021: 5
- FWCI
- 7.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Funders
- HHS | NIH | National Heart, Lung, and Blood Institute (R35HL135820, R01HL105945, R01HL135012)
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (1K01DK120794)
- American Heart Association (16EIA27550005)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- miR-33, SREBP2, conditional knockout mice, obesity, atherosclerosis, HDL cholesterol, reverse cholesterol transport, glucose homeostasis, liver fibrosis, liver inflammation, hyperlipidemia, cardiometabolic disease, cholesterol efflux
- MeSH terms
- Animals, Biological Transport, Body Weight, Carbon Tetrachloride, Cholesterol, Feeding Behavior, Gene Expression Regulation, Homeostasis, Lipoproteins, HDL, Liver, Obesity, MicroRNAs, Atherosclerosis, Mice, Plaque, Atherosclerotic, Diet, High-Fat
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