Abstract
During autophagy, autophagosomes fuse with lysosomes to degrade damaged organelles and misfolded proteins. Breakdown products are released into the cytosol and contribute to energy and metabolic building block supply, especially during starvation. Lipophagy has been defined as the autophagy-mediated degradation of lipid droplets (LDs) by lysosomal acid lipase. Adipose triglyceride lipase (ATGL) is the major enzyme catalyzing the initial step of lipolysis by hydrolyzing triglycerides (TGs) in cytosolic LDs. Consequently, most organs and cells, including macrophages, lacking ATGL accumulate TGs, resulting in reduced intracellular free fatty acid concentrations. Macrophages deficient in hormone-sensitive lipase (H0) lack TG accumulation albeit reduced in vitro TG hydrolase activity. We hypothesized that autophagy is activated in lipase-deficient macrophages to counteract their energy deficit. We therefore generated mice lacking both ATGL and HSL (A0H0). Macrophages from A0H0 mice showed 73% reduced neutral TG hydrolase activity, resulting in TG-rich LD accumulation. Increased expression of cathepsin B, accumulation of LC3-II, reduced expression of p62 and increased DQ-BSA dequenching suggest intact autophagy and functional lysosomes in A0H0 macrophages. Markedly decreased acid TG hydrolase activity and lipid flux independent of bafilomycin A1 treatment, however, argue against effective lysosomal degradation of LDs in A0H0 macrophages. We conclude that autophagy of proteins and cell organelles but not of LDs is active as a compensatory mechanism to circumvent and balance the reduced availability of energy substrates in A0H0 macrophages.
Highlights
Macroautophagy is a lysosomal pathway that degrades superfluous or damaged organelles as well as cytoplasmic inclusions such as misfolded protein aggregates [1]
Genotyping results are shown in Supplemental Fig. S1A; lack of Hormone-sensitive lipase (HSL) and Adipose triglyceride lipase (ATGL) in macrophages was confirmed by Western blot analysis (Supplemental Fig. S1B)
We demonstrate that loss of ATGL reaches a maximal TG accumulation capacity in macrophages, resulting in comparable intracellular TG levels between A0 and A0H0 macrophages
Summary
Macroautophagy (hereafter autophagy) is a lysosomal pathway that degrades superfluous or damaged organelles as well as cytoplasmic inclusions such as misfolded protein aggregates [1]. These cytoplasmic cargos are trapped inside double-membrane vesicles (autophagosomes) that fuse with lysosomes for degradation of their contents. FAs as energy substrates can be released through the autophagic degradation of cytosolic LDs in the lysosome by lysosomal acid lipase (LAL) (a process termed lipophagy) [2] or through intracellular lipolysis by breakdown of TGs. along with lipolysis, autophagy is one of two conserved responses to fasting. The authors argued that inhibition of white adipocyte differentiation may lead to a defect in lipogenesis or that blocked autophagy promotes transdifferentiation from white to brown fat [3]. Acute nutrient starvation was ineffective to induce lipophagy, whereas serum depletion in the presence of amino acids and glucose triggered lipophagy [5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
