The Deficiency of SCARB2/LIMP-2 Impairs Metabolism via Disrupted mTORC1-Dependent Mitochondrial OXPHOS
<p><span class="html-italic">Scarb2<sup>−/−</sup></span> mice show less lipid accumulation on a regular chow diet. (<b>A</b>) Body weights of female WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice on a regular chow diet between 4–17 weeks. <span class="html-italic">n</span> = 7. (<b>B</b>) Body composition of female WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice measured by DEXA after 13 weeks on a regular chow diet. <span class="html-italic">n</span> = 7. (<b>C</b>) Weight of liver, gWAT, scWAT, BAT, spleen of 20-week-old female WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice (<span class="html-italic">n</span> = 3). (<b>D</b>) HE staining of gWAT and scWAT sections from 20-week-old female WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice. Scale bars, 20 μm. (<b>E</b>) HE and Oil Red O staining of BAT sections from 20-week-old female WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice. Scale bars, 20 μm. (<b>F</b>) HE and Oil Red O staining of liver sections from 20-week-old female WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice. Scale bars, 20 μm. DEXA: dual-energy X-ray absorptiometry, scWAT: subcutaneous white adipose tissue, gWAT: gonadal white adipose tissue, BAT: brown adipose tissue. Data are represented as mean ± SEM. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 2
<p>Metabolic phenotype analysis of female <span class="html-italic">Scarb2<sup>−/−</sup></span> mice on a regular chow diet. (<b>A</b>–<b>L</b>) Indirect calorimetry of 16-week-old female WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice: (<b>A</b>,<b>B</b>) VO<sub>2</sub>: oxygen consumption. (<b>C</b>,<b>D</b>) VCO<sub>2</sub>: CO<sub>2</sub> generation. (<b>E</b>,<b>F</b>) RER: respiration exchange rate, VCO<sub>2</sub>/VO<sub>2.</sub> (<b>G</b>,<b>H</b>) HEAT: heat generation. (<b>I</b>,<b>J</b>) Total activity. (<b>K</b>,<b>L</b>) FEED: food intake. <span class="html-italic">n</span> = 7. The line chart represents real time value of 24 h for 2 day average. The column chart represents an average value during the light cycle (8:00~20:00) and dark cycle (20:00~8:00). (<b>M</b>) Food consumption over 24 h of 8-week-old WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice (data represent the average of three days). <span class="html-italic">n</span> = 6 per genotype. (<b>N</b>) Faces weight over 24 h of 8-week-old WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice. <span class="html-italic">n</span> = 6 per genotype. (<b>O</b>) Assessment of energy harvest in 8-week-old WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice fed regular chow diet using fecal bomb calorimetry. <span class="html-italic">n</span> = 6 per genotype. Data are represented as mean ± SEM. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 3
<p><span class="html-italic">Scarb2<sup>Adipoq-cre</sup></span> mice show lower lipid accumulation. (<b>A</b>) Schematic representation of the <span class="html-italic">Scarb2</span> (<b>top</b>), and targeted gene (<b>bottom</b>). (<b>B</b>) The expression of <span class="html-italic">Scarb2</span> in different tissues and organs from <span class="html-italic">Scarb2<sup>Adipoq-cre</sup></span> mice was analyzed by real-time quantitative PCR. Expression levels of target genes were normalized to <span class="html-italic">Rplp0</span> (alias <span class="html-italic">36B4</span>) and data presented in (<b>B</b>) were normalized to the mean value of WT group for each tissue or organ. <span class="html-italic">n</span> = 3. (<b>C</b>) Immunoblot analysis of Scarb2 and β-actin in heart, BAT, gWAT and scWAT from WT and <span class="html-italic">Scarb2<sup>Adipoq-cre</sup></span> mice. <span class="html-italic">n</span> = 4. (<b>D</b>,<b>E</b>) Body composition and percentage of fat mass of female WT and <span class="html-italic">Scarb2<sup>Adipoq-cre</sup></span> mice measured by DEXA after 12 weeks on a regular chow diet. <span class="html-italic">n</span> = 9. (<b>F</b>) HE staining of gWAT, scWAT and BAT sections from 12- week-old female WT and <span class="html-italic">Scarb2<sup>Adipoq-cre</sup></span> mice. Scale bars, 20 μm. (<b>G</b>) HE and Oil Red O staining of BAT sections from 12- week-old female WT and <span class="html-italic">Scarb2<sup>Adipoq-cre</sup></span> mice. Scale bars, 20 μm. DEXA: dual-energy X-ray absorptiometry, scWAT: subcutaneous white adipose tissue, gWAT: gonadal white adipose tissue, BAT: brown adipose tissue. Data are represented as mean ± SEM. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01.</p> "> Figure 4
<p>SCARB2 is not required for adipocyte differentiation. (<b>A</b>) Pictures of differentiated preadipocytes from 10-day-old female WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice on day 0, 2, 4, 6 and 8. Scale bars, 100 μm. (<b>B</b>) Oil Red O staining of differentiated preadipocytes on day 6 and day 8. Scale bars, 100 μm. (<b>C</b>) Statistics of the diameter of adipocytes stained with Oil Red O on day 6 and day 8 from WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice. <span class="html-italic">n</span> = 3. (<b>D</b>) Adipocyte markers <span class="html-italic">Ap2</span>, <span class="html-italic">C/ebpα</span> and <span class="html-italic">Pparγ</span> of differentiated preadipocytes were analyzed by real-time quantitative PCR. Expression levels of target genes were normalized to <span class="html-italic">Rplp0</span> (alias <span class="html-italic">36B4</span>) and data presented in (<b>D</b>) were normalized to the day 0 value of each experiment. <span class="html-italic">n</span> = 3. Data are shown as means ± SEM. * <span class="html-italic">p</span> < 0.05.</p> "> Figure 5
<p>Enhanced glycolysis and impaired oxidative phosphorylation (OXPHOS) in <span class="html-italic">Scarb2<sup>−/−</sup></span> adipocytes. (<b>A</b>) Representative TEM images of WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> WAT from 12- week-old female mice. Scale bar = 0.2 μm in the first column. Scale bar = 0.1 μm in the others. (<b>B</b>) Real-time changes in OCR (a measure of oxidative phosphorylation) of WT or <span class="html-italic">Scarb2<sup>−/−</sup></span> adipocytes measured by Seahorse XF24 Extracellular Flux Analyzer. The compounds (oligomycin, FCCP, and a mix of rotenone and antimycin A) are serially injected to measure ATP production, maximal respiration, and non-mitochondrial respiration, respectively. <span class="html-italic">n</span> = 5. (<b>C</b>) Assessment of basal OCR, ATP production, spare and maximal respiratory capacity of adipocytes in (<b>B</b>). (<b>D</b>) Real-time changes in ECAR (a measure of lactate production and glycolysis) of WT or <span class="html-italic">Scarb2<sup>−/−</sup></span> adipocytes measured by Seahorse XF24 Extracellular Flux Analyzer. The compounds (glucose, oligomycin and 2-DG) are serially injected to measure glycolysis, glycolytic capacity, and non-glycolytic acidification, respectively, which also allows calculation of glycolytic reserve. <span class="html-italic">n</span> = 5. (<b>E</b>) Assessment of glycolysis, glycolytic capacity and glycolytic reserve of adipocytes in (<b>D</b>). OCR: oxygen consumption rate, ECAR: extracellular acidification rate, FCCP: Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone. ATP: Adenosine triphosphate. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 6
<p>mTORC1 pathway is impaired in <span class="html-italic">Scarb2<sup>−/−</sup></span> and <span class="html-italic">Scarb2<sup>Adipoq</sup></span><sup>-cre</sup> WAT. (<b>A</b>) Immunofluorescence of mature adipocytes differentiated from pre-adipocytes of WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice stained with Lysotracker DND-26 (green) and DAPI (blue). Scale bars, 10 μm. (<b>B</b>) The statistical result of mean diameter of lysosomes in pre-adipocytes of WT and Scarb2<sup>−/−</sup> mice. <span class="html-italic">n</span> = 9. (<b>C</b>) Histogram of diameter of lysosomes in pre-adipocytes of WT and Scarb2<sup>−/−</sup> mice. <span class="html-italic">n</span> = 9. (<b>D</b>) Immunoblot analysis of Phos-mTOR (2448 and 2481), Total-mTOR (T-mTOR), Phos-p70s6k, p70s6k, Phos-4ebp1, 4ebp1 and Gapdh in WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mouse WAT was shown. The value of gray scale analysis were calculated by Image J and labeled below bands. Phos-mTOR (2448), Phos-mTOR (2481), Phos-p70s6k and Phos-4ebp1 were normalized to the respective total protein, p70s6k, T-mTOR and 4ebp1 were normalized to GAPDH. (<b>E</b>) Immunoblot analysis of Phos-p70s6k, p70s6k, Phos-4ebp1, 4ebp1 and Gapdh in gWAT or scWAT of WT and <span class="html-italic">Scarb2<sup>Adipoq</sup></span><sup>-cre</sup> mice was shown. (<b>F</b>,<b>G</b>) The gray scale analysis of phos-s6k/s6k and phos-4e-bp1/4e-bp1 in (<b>E</b>). All the data were normalized to the mean value of phos-s6k/s6k or phos-4e-bp1/4e-bp1 in WT group, respectively. (<b>H</b>) Immunoblot analysis of Tfam and Gapdh in gWAT or scWAT of WT, <span class="html-italic">Scarb2<sup>−/−</sup></span> and <span class="html-italic">Scarb2<sup>Adipoq</sup></span><sup>-cre</sup> mice was shown. (<b>I</b>,<b>J</b>) The gray scale analysis of Tfam /Gapdh in (<b>H</b>). All the data were normalized to the mean value of Tfam /Gapdh in WT group. (<b>K</b>) The mRNA levels of <span class="html-italic">Tfam</span> in WAT of WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> mice analyzed by real-time quantitative PCR. <span class="html-italic">n</span> = 4. Expression levels of target genes were normalized to <span class="html-italic">Rplp0</span> (alias <span class="html-italic">36B4</span>). All the data were normalized to the mean value of WT group. (<b>L</b>) The mRNA levels of <span class="html-italic">Tfam</span> in WAT of WT and <span class="html-italic">Scarb2<sup>Adipoq</sup></span><sup>-cre</sup> mice analyzed by real-time quantitative PCR. <span class="html-italic">n</span> = 4. Expression levels of target genes were normalized to <span class="html-italic">Rplp0</span> (alias <span class="html-italic">36B4</span>). All the data were normalized to the mean value of WT group. scWAT: subcutaneous white adipose tissue, gWAT: gonadal white adipose tissue. Data are shown as means ± SEM. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 7
<p>Activation of mTORC1 rescues impaired OXPHOS in <span class="html-italic">Scarb2<sup>−/−</sup></span> adipocytes. (<b>A</b>) Real-time changes in OCR (a measure of oxidative phosphorylation) of WT, <span class="html-italic">Scarb2<sup>−/−</sup></span> adipocytes and <span class="html-italic">Scarb2<sup>−/−</sup></span> adipocytes treated with 0.5 mM Leucine measured by Seahorse XF24 Extracellular Flux Analyzer. The compounds (oligomycin, FCCP and a mix of rotenone and antimycin A) are serially injected to measure ATP production, maximal respiration, and non-mitochondrial respiration, respectively. <span class="html-italic">n</span> = 5. (<b>B</b>) Assessment of basal OCR, ATP production, spare and maximal respiratory capacity of adipocytes in (<b>A</b>). (<b>C</b>) Real-time changes in ECAR (a measure of lactate production and glycolysis) of WT, <span class="html-italic">Scarb2<sup>−/−</sup></span> adipocytes and <span class="html-italic">Scarb2<sup>−/−</sup></span> adipocytes treated with 0.5 mM Leucine measured by Seahorse XF24 Extracellular Flux Analyzer. The compounds (glucose, oligomycin, and 2-DG) are serially injected to measure glycolysis, glycolytic capacity, and non-glycolytic acidification, respectively, which allows calculation of glycolytic reserve. <span class="html-italic">n</span> = 5. (<b>D</b>) Assessment of glycolysis, glycolytic capacity and glycolytic reserve of adipocytes in (<b>C</b>). For <span class="html-italic">Scarb2<sup>−/−</sup></span> +0.5 mM Leucine group: 0.5 mM Leucine (final concentration) was added in Seahorse media, as the activator of the mTORC1 pathway. <span class="html-italic">Scarb2<sup>−/−</sup></span> + 0.5 mM adipocytes were also pre-treated with 0.5 mM Leucine in media (final concentration) for 24 h before the Seahorse experiments. (<b>E</b>) Immunoblot analysis of HA, Phos-p70s6k, p70s6k, Phos-4ebp1, 4ebp1 and Gapdh in WT and <span class="html-italic">Scarb2<sup>−/−</sup></span> MEFs are shown. Scarb2 was overexpressed in <span class="html-italic">Scarb2<sup>−/−</sup></span> MEFs by transfecting plasmid pCDNA5-HA-Scarb2. EXO1 and Brefeldin A (BFA) are two inhibitors of protein trafficking. 90 microM EXO1 (final concentration) and 5 microM BFA (final concentration) was added in media respectively for 24 h before harvest. (<b>F</b>) Real-time changes in OCR (a measure of oxidative phosphorylation) of WT, <span class="html-italic">Scarb2<sup>−/−</sup></span> MEFs and <span class="html-italic">Scarb2<sup>−/−</sup></span> MEFs overexpressed Scarb2 measured by Seahorse XF24 Extracellular Flux Analyzer. The compounds (oligomycin, FCCP, and a mix of rotenone and antimycin A) are serially injected to measure ATP production, maximal respiration, and non-mitochondrial respiration, respectively. <span class="html-italic">n</span> = 5. (<b>G</b>) Real-time changes in ECAR (a measure of lactate production and glycolysis) of WT, <span class="html-italic">Scarb2<sup>−/−</sup></span> MEFs and <span class="html-italic">Scarb2<sup>−/−</sup></span> MEFs overexpressed Scarb2 measured by Seahorse XF24 Extracellular Flux Analyzer. The compounds (glucose, oligomycin, and 2-DG) are serially injected to measure glycolysis, glycolytic capacity, and non-glycolytic acidification, respectively, which allows calculation of glycolytic reserve. <span class="html-italic">n</span> = 5. (<b>H</b>) Assessment of basal OCR, ATP production, spare and maximal respiratory capacity of MEFs in (<b>F</b>). (<b>I</b>) Assessment of glycolysis, glycolytic capacity and glycolytic reserve in MEFs were calculated based on (<b>G</b>). For <span class="html-italic">Scarb2<sup>−/−</sup></span> +Scarb2 group: Scarb2 was overexpressed in <span class="html-italic">Scarb2<sup>−/−</sup></span> MEFs by transfecting plasmid pCDNA5-HA-Scarb2. MEFs: mouse embryonic fibroblast cells. OCR: oxygen consumption rate, ECAR: extracellular acidification rate, FCCP: Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone, ATP: Adenosine triphosphate. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 8
<p>Model graph proposing the changes of lysosomes and mitochondria brought by the absence of SCARB2. The normal activation of mTORC1 was disrupted at the surface of swollen lysosome as a consequence of Scarb2 deficiency, leading to changes in the mTORC1 pathway with decreased phosphorylation of mTORC1 and 4E-BPs. Thus, the expression of Tfam was down-regulated and the ability to produce ATP by mitochondrial oxidative phosphorylation was reduced. The impaired OXPHOS and increased glycolysis leads to the waste of energy, resulting in less lipid accumulation and less fat mass in <span class="html-italic">Scarb2<sup>−/−</sup></span> mice.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Scarb2−/− Mice Show Less Lipid Accumulation
2.2. The Less Lipid Accumulation in Scarb2−/− Mice Is Independent of Heat Production, Activity, Food Intake and Energy Absorption
2.3. The Less Lipid Accumulation in Scarb2−/− Mice Is Independent of Cholesterol Metabolism
2.4. The Deficiency of Scarb2 in Adipocytes Contribute to the Less Lipid Accumulation
2.5. The Less Lipid Accumulation Is Independent of Adipocyte Differentiation
2.6. Enhanced Glycolysis and Impaired Oxidative Phosphorylation (OXPHOS) in Scarb2−/− Adipocytes
2.7. Abnormal Lysosomes and Dysregulated mTORC1 Pathway in Scarb2−/− Adipocytes
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. Cell Culture
4.3. Isolation of Pre-Adipocytes Cells and Adipocyte Differentiation
4.4. Histology
4.5. Food Intake
4.6. Energy Expenditure and Body Composition Analysis
4.7. Bomb Calorimetry
4.8. Plasmids
4.9. Antibodies and Reagents
4.10. Western Blotting
4.11. Real-Time Quantitative PCR Analysis
4.12. Transmission Electron Microscopy
4.13. Seahorse Extracellular Flux Assays
4.14. Lysosomes Detection
4.15. Statistics
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Primer Name | Forward Sequence | Reverse Sequence |
---|---|---|
36B4 | TAAAGACTGGAGACAAGGTG | GTGTACTCAGTCTCCACAGA |
C/EBPα | CAAGAACAGCAACGAGTACCG | GTCACTGGTCAACTCCAGCAC |
PPARγ | TCGCTGATGCACTGCCTATG | GAGAGGTCCACAGAGCTGATT |
Ap2 | AGCTGGTGGTGGAATGTGTT | AATTTCCATCCAGGCCTCTT |
Tfam | GGAATGTGGAGCGTGCTAAAA | ACAAGACTGATAGACGAGGGG |
Scarb2 | AGAAGGCGGTAGACCAGAC | GTAGGGGGATTTCTCCTTGGA |
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Zou, Y.; Pei, J.; Wang, Y.; Chen, Q.; Sun, M.; Kang, L.; Zhang, X.; Zhang, L.; Gao, X.; Lin, Z. The Deficiency of SCARB2/LIMP-2 Impairs Metabolism via Disrupted mTORC1-Dependent Mitochondrial OXPHOS. Int. J. Mol. Sci. 2022, 23, 8634. https://doi.org/10.3390/ijms23158634
Zou Y, Pei J, Wang Y, Chen Q, Sun M, Kang L, Zhang X, Zhang L, Gao X, Lin Z. The Deficiency of SCARB2/LIMP-2 Impairs Metabolism via Disrupted mTORC1-Dependent Mitochondrial OXPHOS. International Journal of Molecular Sciences. 2022; 23(15):8634. https://doi.org/10.3390/ijms23158634
Chicago/Turabian StyleZou, Yujie, Jingwen Pei, Yushu Wang, Qin Chen, Minli Sun, Lulu Kang, Xuyuan Zhang, Liguo Zhang, Xiang Gao, and Zhaoyu Lin. 2022. "The Deficiency of SCARB2/LIMP-2 Impairs Metabolism via Disrupted mTORC1-Dependent Mitochondrial OXPHOS" International Journal of Molecular Sciences 23, no. 15: 8634. https://doi.org/10.3390/ijms23158634