Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes
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Curated by eLife
Evaluation Summary:
This study addresses the the potential effects of saturated vs. unsaturated fatty acids on kidney proximal tubule injury in diabetic kidney disease. They find that compared to saturated fatty acids, unsaturated fatty acids prevent ER stress by stimulating triacylglycerol formation.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
In diabetic patients, dyslipidemia frequently contributes to organ damage such as diabetic kidney disease (DKD). Dyslipidemia is associated with both excessive deposition of triacylglycerol (TAG) in lipid droplets (LDs) and lipotoxicity. Yet, it is unclear how these two effects correlate with each other in the kidney and how they are influenced by dietary patterns. By using a diabetes mouse model, we find here that high-fat diet enriched in the monounsaturated oleic acid (OA) caused more lipid storage in LDs in renal proximal tubular cells (PTCs) but less tubular damage than a corresponding butter diet with the saturated palmitic acid (PA). This effect was particularly evident in S2/S3 but not S1 segments of the proximal tubule. Combining transcriptomics, lipidomics, and functional studies, we identify endoplasmic reticulum (ER) stress as the main cause of PA-induced PTC injury. Mechanistically, ER stress is caused by elevated levels of saturated TAG precursors, reduced LD formation, and, consequently, higher membrane order in the ER. Simultaneous addition of OA rescues the cytotoxic effects by normalizing membrane order and increasing both TAG and LD formation. Our study thus emphasizes the importance of monounsaturated fatty acids for the dietary management of DKD by preventing lipid bilayer stress in the ER and promoting TAG and LD formation in PTCs.
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Evaluation Summary:
This study addresses the the potential effects of saturated vs. unsaturated fatty acids on kidney proximal tubule injury in diabetic kidney disease. They find that compared to saturated fatty acids, unsaturated fatty acids prevent ER stress by stimulating triacylglycerol formation.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
The manuscript addresses the role of different lipids on diabetic kidney disease (DKD). It is known that lipids can have a negative impact on DKD, but little is known about different lipids and potential mechanisms triggered. This open question is addressed by the authors and their provide new insights by showing that different lipids affect the ER-stress response differentially. A limitation of the study is that mechanistic studies are limited to in vitro work, leaving the question to which extend the identified mechanisms would be relevant in vivo open. A strength is the combined transriptomics and lipidomics analyses. More details regarding membrane fluidity - using different techniques - will be required in the future.
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Reviewer #2 (Public Review):
This study examined the potential role of unsaturated fatty acids (MUFA) vs. saturated fatty acids (SFA) in mediation of kidney proximal tubule injury in a model of diabetes. Utilizing cultured proximal tubule cells, they find that MUFA led to increased tubule lipid droplets by stimulating triacylglycerol formation and prevented injury by decreasing ER stress compared to SFA. Of note simultaneous administration of MUFA still inhibited the effect of SFA.
This is a very complete study utilizing a combination of animal models, transcriptomic analysis and lipidomics. In general, the results appear consistent and the studies appear to be well performed. The authors have attempted to investigate underlying mechanisms relating to the observed phenomena. They demonstrate and increase in tubule injury and …
Reviewer #2 (Public Review):
This study examined the potential role of unsaturated fatty acids (MUFA) vs. saturated fatty acids (SFA) in mediation of kidney proximal tubule injury in a model of diabetes. Utilizing cultured proximal tubule cells, they find that MUFA led to increased tubule lipid droplets by stimulating triacylglycerol formation and prevented injury by decreasing ER stress compared to SFA. Of note simultaneous administration of MUFA still inhibited the effect of SFA.
This is a very complete study utilizing a combination of animal models, transcriptomic analysis and lipidomics. In general, the results appear consistent and the studies appear to be well performed. The authors have attempted to investigate underlying mechanisms relating to the observed phenomena. They demonstrate and increase in tubule injury and interstitial fibrosis in the mouse model and that SFA induce ER stress. There remains some uncertainty about the mechanism by which MUFA inhibit injury by simultaneous addition of SFA. although the authors postulate it is due in part to increased TGA formation, the protective effect remained even with dacylglycerol transferase inhibition. There are also some other addressable issues.
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Reviewer #3 (Public Review):
Strengths:
The work presents the interesting and novel hypothesis that like fat cells, kidney cells have the capacity to accumulate and store surplus lipids without incurring damage common to most non-adipose cells overloaded with excess lipids.
Using state of the art methodologies, the study makes the compelling case that the pathways for the formation and function of the storage lipid droplets depends on the type of lipid. Unsaturated oleic acid found in olive oil promotes more lipid storage in kidney cells associated with less cellular toxicity while saturated palmitic acid commonly found in butter-rich diets causes less lipid accumulation but more toxicity. The concept is supported by studies showing concurrently added oleic acid can protect cells against palmitic acid-induced cell damage.
The work is …
Reviewer #3 (Public Review):
Strengths:
The work presents the interesting and novel hypothesis that like fat cells, kidney cells have the capacity to accumulate and store surplus lipids without incurring damage common to most non-adipose cells overloaded with excess lipids.
Using state of the art methodologies, the study makes the compelling case that the pathways for the formation and function of the storage lipid droplets depends on the type of lipid. Unsaturated oleic acid found in olive oil promotes more lipid storage in kidney cells associated with less cellular toxicity while saturated palmitic acid commonly found in butter-rich diets causes less lipid accumulation but more toxicity. The concept is supported by studies showing concurrently added oleic acid can protect cells against palmitic acid-induced cell damage.
The work is timely as there is increasing recognition that lipotoxicity transcends documentation of elevated levels by traditional lipid panels, e.g., total cholesterol, lipoproteins, and triglycerides. Moreover, since lipotoxicity occurs in most, if not all kidney diseases, understanding the pathways for channeling different lipids into cellular structures, mitochondrial -oxidation, or lipid droplets may become useful in developing therapeutic approaches to treating these conditions.
Weaknesses:
Although both butter and olive oil enriched diets increased kidney lipids animals with diabetic nephropathy, lipid accumulation was stronger in olive oil-fed mice compared to butter-fed mice, yet tubular damage was less. This observation forms the basis for the conclusion that monounsaturated olive oil diet has a protective role by increasing lipid storage in lipid droplets. The cause and effect of this critical conclusion should have additional support clearly demonstrating and quantitating lipid droplets within the kidney tissue along with evidence of damage in the lipid-loaded kidney cells.
The design of the studies does not adequately link the in vivo observations in the animal model of diabetic nephropathy with in vitro studies delving into the cellular response to palmitic and oleic acid driven injuries. For example, the possible effects of high glucose levels prevailing in diabetes is not included in lipid metabolic studies in cultured kidney cells.
Lipid accumulation within the kidney tissue is clearly not uniform. However, the heterogeneous handling of palmitate and oleate among kidney cells is not accounted for in the experimental design.
Lipid droplet formation follows a predictable path for handling excess fatty acids in a variety of cells and is well described in the existing literature. More direct support that lipid droplets formation are indeed protective in kidney cells is needed together with discussion of how this is different in kidney cells.
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