Hepatic Lipid Catabolism via PPARα-Lysosomal Crosstalk
Round 1
Reviewer 1 Report
Dear Editor,
The review submitted by Sinha and Co is a well-compiled review about the bidirectional interplay between PPAR alpha and lysosome machinery.
The review addressed the important issue about the targeted therapy of liver disease using PPAR agonists. There are few updated reviews on the same topic available emphasizing the relevance of the topic.
I have only a few issues need to be addressed before the review gets published.
Autophagy is strongly involved in the tissue aging process. It will be great if authors add information about the role of PPAR alpha impairment in aging and correlation to the autophagy.
The regulation of PPAR alpha is well known to be mediated by posttranslational modification (mainly MAPK). The lysosome trafficking, organelles targeting and biogenesis is also regulated by phosphorylation. The authors need to include this aspect in there suggested mechanistic paradigm.
As authors suggested the activation of PPAR alpha induces lipid droplets degradation. The associated lipid droplets protein (KLF) is known to be involved in the regulation of PPAR transcription. The authors need to discuss the KLF_PPAR regulatory axis as well in the context of the suggested mechanism in the same context (figure 1B).
The authors have already mentioned that the clinical efforts using PPAR agonists on humans didn't work well. The authors need to argue the potential issues about the not sufficient efficacy of the application of the PPAR agonists in clinical trials and discuss alternative strategies to improve it.
Sincerely
Author Response
Reviewer's Comment: The review submitted by Sinha and Co is a well-compiled review about the bidirectional interplay between PPAR alpha and lysosome machinery.The review addressed the important issue about the targeted therapy of liver disease using PPAR agonists. There are few updated reviews on the same topic available emphasizing the relevance of the topic.
Response: We are thankful to the reviewer for his positive comments.
Reviewer's Comment:
Autophagy is strongly involved in the tissue aging process. It will be great if authors add information about the role of PPAR alpha impairment in aging and correlation to the autophagy.
Response: As suggested by the reviewer we have included this point at line 312-315 in the revised version.
Reviewer's Comment:
The regulation of PPAR alpha is well known to be mediated by posttranslational modification (mainly MAPK). The lysosome trafficking, organelles targeting and biogenesis is also regulated by phosphorylation. The authors need to include this aspect in there suggested mechanistic paradigm.
Response: As suggested by the reviewer we have included this point at line 170-172 in the revised version.
Reviewer's Comment:
As authors suggested the activation of PPAR alpha induces lipid droplets degradation. The associated lipid droplets protein (KLF) is known to be involved in the regulation of PPAR transcription. The authors need to discuss the KLF_PPAR regulatory axis as well in the context of the suggested mechanism in the same context (figure 1B).
Response: We agree with this interesting point raised by the reviewer, however since we are more focused on the hepatic lipophagy and PPARa interaction we have omitted the KLF angle in the present manuscript which has more implications in PPAR regulation in adipocytes.
Reviewer's Comment:
The authors have already mentioned that the clinical efforts using PPAR agonists on humans didn't work well. The authors need to argue the potential issues about the not sufficient efficacy of the application of the PPAR agonists in clinical trials and discuss alternative strategies to improve it.
Response: We have now addressed this issue in our revised manuscript as suggested by the reviewer.
Reviewer 2 Report
The review article summarized the recent findings of the role of lipophagy in hepatic lipid metabolism via PPARα. It is a well written manuscript. I only have few minor suggestions:
- page 1 line 33, predominant (iso)form in liver
- Figure legend of figure 1, leads to both increased stability
- Need to further improve Figure 1. E.g., for 1A, it fails to show PPARα regulating the expression of Atg genes at transcription level. For B, any special meanings for different kind of arrows were used?
- page 7 line 298, time-restriction feeding
- page 8 line 321, delete "our studies also suggest that ....other nuclear receptors". Unless, authors clearly highlighted their related works in this manuscript. Otherwise, it is not appropriate to do so.
Author Response
Reviewer's Comment:The review article summarized the recent findings of the role of lipophagy in hepatic lipid metabolism via PPARα. It is a well written manuscript.
Response: We are thankful to the reviewer for his positive comments on our review.
Reviewer's Comments:
- page 1 line 33, predominant (iso)form in liver
- Figure legend of figure 1, leads to both increased stability
- Need to further improve Figure 1. E.g., for 1A, it fails to show PPARα regulating the expression of Atg genes at transcription level. For B, any special meanings for different kind of arrows were used?
- page 7 line 298, time-restriction feeding
- page 8 line 321, delete "our studies also suggest that ....other nuclear receptors". Unless, authors clearly highlighted their related works in this manuscript. Otherwise, it is not appropriate to do so.
Response: All the corrections suggested above have been incorporated in the revised manuscript.
Reviewer 3 Report
Sinha, et al reviewed hepatic lipid catabolism via PPARα-Lysosomal 2 crosstalk. The theme is very interesting and the description of the text is very well done. The authors described the basics of lipophagy as well as the overall relationship between PPAR-a and lipophagy. However, the authors need to make up for the points mentioned below.
1. In Fig. 1a, the basic concept of lipophagy is illustrated and explained well. In general, autophagosomes fusion with lysosomes to form autolysosomes, and then lipolysis of lipid droplets by lysosome lipase. However, only the lysosome is shown in Fig. 1a, which can confuse readers in understanding it correctly. In addition, Fig1a is too similar to the fig. of other papers, which may cause copyright problems. (Int J Cell Biol. 2012;2012:282041). Therefore, it is necessary to modify the figure as a whole.
2. Page7. The statements made by the authors in lines 284-286 are not relevant. Currently, AASLD, EASL and other guidelines do not recommend the use of PPAR-a agonist as a treatment in patients with NAFLD or NASH. In practice, doctors do not prescribe a PPAR-a agonist, or fenofibrate, if patients with NAFLD or NASH do not have hypertriglyceridemia.
Author Response
Reviewer's Comments:
Sinha, et al reviewed hepatic lipid catabolism via PPARα-Lysosomal 2 crosstalk. The theme is very interesting and the description of the text is very well done. The authors described the basics of lipophagy as well as the overall relationship between PPAR-a and lipophagy. However, the authors need to make up for the points mentioned below.
Response: We are grateful to the reviewer for his positive comments.
Reviewer's comments:
- In Fig. 1a, the basic concept of lipophagy is illustrated and explained well. In general, autophagosomes fusion with lysosomes to form autolysosomes, and then lipolysis of lipid droplets by lysosome lipase. However, only the lysosome is shown in Fig. 1a, which can confuse readers in understanding it correctly. In addition, Fig1a is too similar to the fig. of other papers, which may cause copyright problems. (Int J Cell Biol. 2012;2012:282041). Therefore, it is necessary to modify the figure as a whole.
Response: We have now corrected and modify our figure accordingly.
Reviewer's Comments:
2. Page7. The statements made by the authors in lines 284-286 are not relevant. Currently, AASLD, EASL and other guidelines do not recommend the use of PPAR-a agonist as a treatment in patients with NAFLD or NASH. In practice, doctors do not prescribe a PPAR-a agonist, or fenofibrate, if patients with NAFLD or NASH do not have hypertriglyceridemia.
Response: We have now corrected and modify our statement accordingly to remove the ambiguity as indicated by the reviewer.
