PONE-D-19-23129

Apoplipoprotein-AI mimetic peptides D-4F and L-5F decrease hepatic inflammation and increase insulin sensitivity in C57BL/6 mice

PLOS ONE

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Reviewer #1: Manuscript Number: PONE-D-19-23129

Apoplipoprotein-AI mimetic peptides D-4F and L-5F decrease hepatic inflammation and increase insulin sensitivity in C57BL/6 mice by Kristine Ching-Yee McGrath et al.

The present manuscript has been described that D-4F and L-5F, the Apo-AI mimetic peptides treatment led to improved glucose homeostasis, and this effect is associated with reduced expression of inflammatory markers in the liver and reduced infiltration of macrophages, suggesting an overall suppression of hepatic inflammation.

These observations are interesting, and some specific point should be considered.

Specific comments

Authors have described only D-4F and L-5F as Apo-AI mimetic peptides, however various Apo-AI mimetic peptides have been developed so far. Authors should show about other peptides such as 5A, 18A, and FAMP...

In addition to Apo-AI mimetic peptides, we also have reconstituted-HDL such as ApoA-1/POPC disc. Author should describe the difference between Apo-AI mimetic peptides and reconstituted-HDL.

In this study, the authors conducted i.p.GTT as an assessment of glucose tolerance, but this method neglected the effects of incretin. Is it not necessary to consider the effect of incretin on the results of this study?

CETP inhibitor, one of the HDL-targeting drug also improves glucose homeostasis. The authors should consider the difference in the mechanism between the effect of CETP inhibitor and the effect of Apo-AI mimetic peptides.

HOMA-IR and HOMA-beta should be shown.

Fig. 1A; 4A; 4B; 5A; 6A; 6B, It is very difficult to understand group differences in the line graphs.

Reviewer #2: Interesting paper examining effect of apoA-I mimetic peptides (D4F and L5F) on glucose metabolism in C57BL6 mice fed a high fat diet.

1. Abstract: Quantitative description of key findings and P-values should be added.

2. Methods: Method used to quantify visceral and SQ fat should be stated. Time from. Last peptide dose for drawing plasma from mice should be stated.

3. Lipoprotein analysis: Ideally, besides plasma triglycerides, total cholesterol should also be analyzed. A more detailed analysis of plasma lipoproteins would also be helpful.

4. Discussion: Short paragraph should be added on potential mechanism of action of peptides in regard to observed effects. Oral D4F has been proposed to act via modulating oxidized lipid content in the intestine. This works should be cited and used to possibly explain effect of D4F and lack of effect of L5F. Should discuss how the magnitude of the effect on glucose metabolism by D4F compares to past studies on treatment with rHDL.

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Reviewer #1: No

Reviewer #2: No

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Apoplipoprotein-AI mimetic peptides D-4F and L-5F decrease hepatic inflammation and increase insulin sensitivity in C57BL/6 mice

PONE-D-19-23129R1

Dear Dr. McGrath,

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