Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis
Yu-Sheng Yeh, Trent D. Evans, Mari Iwase, Se-Jin Jeong, Xiangyu Zhang, Ziyang Liu, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Dagmar Kratky, Satoko Kawarasaki, Tsuyoshi Goto, Hanrui Zhang, Partha Dutta, Francisco J. Schopfer, Adam C. Straub, Jaehyung Cho, Irfan J. Lodhi, Babak Razani
Yu-Sheng Yeh, Trent D. Evans, Mari Iwase, Se-Jin Jeong, Xiangyu Zhang, Ziyang Liu, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Dagmar Kratky, Satoko Kawarasaki, Tsuyoshi Goto, Hanrui Zhang, Partha Dutta, Francisco J. Schopfer, Adam C. Straub, Jaehyung Cho, Irfan J. Lodhi, Babak Razani
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Research Article Endocrinology Metabolism

Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis

Abstract

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

Yu-Sheng Yeh, Trent D. Evans, Mari Iwase, Se-Jin Jeong, Xiangyu Zhang, Ziyang Liu, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Dagmar Kratky, Satoko Kawarasaki, Tsuyoshi Goto, Hanrui Zhang, Partha Dutta, Francisco J. Schopfer, Adam C. Straub, Jaehyung Cho, Irfan J. Lodhi, Babak Razani

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Figure 2

LIPA disruption suppresses fasting-, cold-, and β-agonist-induced lipolysis in mouse models.

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LIPA disruption suppresses fasting-, cold-, and β-agonist-induced lipoly...
(A) Experimental strategy outlining Adipoq-Cre–driven knockout of LIPA to generate A-Lipa KO mice. (B) Characterization of LIPA depletion at the mRNA (n = 7 in iWAT; n = 3 in BAT, eWAT and liver) and (C) protein levels in tissues from control (Ctrl) versus A-Lipa KO mice. (D) Lipa gene expression in homogenized eWAT separated by centrifugation into floating adipocyte and pelleted SV fractions from control (n = 6) and A-Lipa KO (n = 7) mice. (E) Schematic illustration of lipolysis assay by using genetic knockout mice model, A-Lipa KO mice, or pharmacological inhibition via lalistat-2 treatment. (F) Plasma FFA levels were measured at indicated time points in fasted A-Lipa KO and control mice (n = 12) (left) or in C57BL/6J mice fasted for 16 hours and injected intraperitoneally with 30 mg/kg lalistat-2 (n = 11) or vehicle (n = 10), followed by an additional 4 hours fasting. (G) Plasma FFA measured in A-Lipa KO and control mice (n = 4 each) fasted and individually housed at 4°C for indicated time points (left panel) or in C57BL/6J mice (n = 9 or 11) injected with 30 mg/kg lalistat-2 or vehicle 1 hour prior to fasting and individual housing at 4°C (right panel). (H) Plasma FFA (n = 4) measured at indicated time points in A-Lipa KO and control mice fasted for 16 hours then intraperitoneally injected with 1 mg/kg CL (left panel) or in C57BL/6J mice fasted for 16 hours, injected with 30 mg/kg lalistat-2 (n = 9) or vehicle (n = 8), and fasted for an additional 90 minutes prior to administration of 1 mg/kg CL without refeeding for indicated durations (right panel). All mice were male and fed an ND. Values are presented as mean ± SEM. Significant differences were determined by Student’s t test compared with their control group. *P < 0.05; **P < 0.01; ***P < 0.001. See also Supplemental Figures 4–10.