A controlled-release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice
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Lipodystrophy is a rare disorder characterized by complete or partial loss of adipose tissue. Patients with lipodystrophy exhibit hypertriglyceridemia, severe insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). Efforts to ameliorate NASH in lipodystrophies with pharmacologic agents have met with limited success. We examined whether a controlled-release mitochondrial protonophore (CRMP) that produces mild liver-targeted mitochondrial uncoupling could decrease hypertriglyceridemia and reverse NASH and diabetes in a mouse model (fatless AZIP/F-1 mice) of severe lipodystrophy and diabetes. After 4 wk of oral CRMP (2 mg/kg body weight per day) or vehicle treatment, mice underwent hyperinsulinemic-euglycemic clamps combined with radiolabeled glucose to assess liver and muscle insulin responsiveness and tissue lipid measurements. CRMP treatment reversed hypertriglyceridemia and insulin resistance in liver and skeletal muscle. Reversal of insulin resistance could be attributed to reductions in diacylglycerol content and reduced PKC-ε and PKC-θ activity in liver and muscle respectively. CRMP treatment also reversed NASH as reflected by reductions in plasma aspartate aminotransferase and alanine aminotransferase concentrations; hepatic steatosis; and hepatic expression of IL-1α, -β, -2, -4, -6, -10, -12, CD69, and caspase 3 and attenuated activation of the IRE-1α branch of the unfolded protein response. Taken together, these results provide proof of concept for the development of liver-targeted mitochondrial uncoupling agents as a potential novel therapy for lipodystrophy-associated hypertriglyceridemia, NASH and diabetes.-Abulizi, A., Perry, R. J., Camporez, J. P. G., Jurczak, M. J., Petersen, K. F., Aspichueta, P., Shulman, G. I. A controlled-release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice.
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Similar effects of DNP treatment have been reported in lipodystrophic mice (AZIP/F-1).
“Similar effects of this treatment have also been reported by the same group in lipodystrophic mice (AZIP/F-1), a mouse model expressing the A-ZIP/F gene under the control of the Fabp4 promoter characterized by a virtually complete absence of white adipose tissue [278].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [278]
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- Authors
- Abulizi, A., Perry, R. J., Camporez, J. P. G., Jurczak, M. J., Petersen, K. F., Aspichueta, P., & Shulman, G. I.
- Affiliations
- Yale University (US)
- University of the Basque Country (ES)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shulman, Gerald I.
- ORCID
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2017-03-22
- Volume
- 31
- Issue
- 7
- Pages
- 2916-2924
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC5471523
- OpenAlex
- W2600136923
- Cited by
- 41
- References
- 34
- Citations by year
- 2026: 2 · 2024: 5 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 6 · 2019: 11 · 2018: 6 · 2017: 3
- FWCI
- 5.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK40936)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- lipodystrophy, hypertriglyceridemia, nonalcoholic steatohepatitis, type 2 diabetes, mitochondrial uncoupling, controlled drug delivery, insulin resistance, hepatic steatosis, diacylglycerol, protein kinase C, unfolded protein response, IRE1α, inflammation
- MeSH terms
- Animals, Delayed-Action Preparations, Diabetes Mellitus, Type 2, Eating, Energy Metabolism, Insulin Resistance, Lipodystrophy, Male, Mitochondria, Liver, Random Allocation, Hypertriglyceridemia, Mice, Proton Ionophores, Non-alcoholic Fatty Liver Disease
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