Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis
Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. Furthermore, adipocyte LIPA deficiency impaired thermogenesis and oxygen consumption and rendered mice susceptible to diet-induced obesity. Importantly, lysosomal lipolysis was independent of adipose triglyceride lipase, the rate-limiting enzyme of cytosolic lipolysis. Our data suggest a significant role for LIPA and lysosomal lipolysis in adipocyte lipid metabolism beyond classical cytosolic lipolysis.
Authors
- Ali Javaheri (ORCID: https://orcid.org/0000-0001-6657-331X)
- Irfan J. Lodhi (ORCID: https://orcid.org/0000-0002-6246-9862)
- Satoko Kawarasaki (ORCID: https://orcid.org/0000-0001-7620-8930)
- Yu‐Sheng Yeh (ORCID: https://orcid.org/0000-0002-0099-2690)
- Hanrui Zhang (ORCID: https://orcid.org/0000-0001-8655-938X)
- Se‐Jin Jeong
- Dagmar Kratky (ORCID: https://orcid.org/0000-0003-1357-7573)
- Francisco J. Schöpfer (ORCID: https://orcid.org/0000-0001-9526-695X)
- Arick Park
- Jaehyung Cho (ORCID: https://orcid.org/0000-0003-2404-3446)
- Partha Dutta (ORCID: https://orcid.org/0000-0001-7456-1757)
- Mari Iwase (ORCID: https://orcid.org/0000-0002-6494-8787)
- Adam C. Straub (ORCID: https://orcid.org/0000-0003-0542-9466)
- Babak Razani (ORCID: https://orcid.org/0000-0002-7172-9240)
- Trent D. Evans (ORCID: https://orcid.org/0000-0003-1809-444X)
- Xiangyu Zhang (ORCID: https://orcid.org/0000-0001-5350-5879)
- Ziyang Liu (ORCID: https://orcid.org/0000-0002-3067-9523)
- Tsuyoshi Goto (ORCID: https://orcid.org/0000-0003-1283-147X)
- Ali Ghasemian
- Borna Dianati
Institutions
- University of Pittsburgh (US)
- Medical University of Graz (AT)
- Washington University in St. Louis (US)
- Kyoto University (JP)
- Columbia University Irving Medical Center (US)
- UPMC Health System (US)
- University of Pittsburgh Medical Center (US)
- John Cochran VA Medical Center (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-03-16
- DOI
- https://doi.org/10.1172/jci185340
- Citations
- 6
- Primary Topic
- Lipid metabolism and biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 6.67
Funders
- U.S. Department of Veterans Affairs
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute