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Merscher, S.

Publications and source records attributed to Merscher, S..

2 recordsLinked to original sources
bioRxiv2025

Novel Lipophagy Inducers as Potential Therapeutics for Lipid Metabolism Disorders

Dysregulation of lipid homeostasis is associated with a wide range of pathologies encompassing neurological, metabolic, cardiovascular, oncological, and renal disorders. We previously showed that lipid droplet (LD) accumulation in podocytes contributes to the progression of diabetic kidney disease (DKD) and reducing LDs preserves podocyte function and prevents albuminuria. Here, we sought to identify compounds that treat pathological LD accumulation. We developed a phenotypic assay using human podocytes and deployed it to screen a combinatorial library comprising over 45 million unique small molecules. This led to the identification of a compound series that effectively reduce LD accumulation in stressed podocytes. Mechanistic studies revealed that these compounds activate lipophagy, reduce LD accumulation, and rescue podocytes from cell death. In contrast, compounds known to induce general autophagy failed to mimic these effects, indicating a novel lipophagy-specific mechanism of action (MoA), which was confirmed with unbiased phenotypic profiling. An advantage of this therapeutic strategy is its potential to not only halt the progression of pathological lipid accumulation but also reverse it. These compounds will serve as tools for uncovering novel drug targets and therapeutic MoAs for treating DKD and other diseases with similar etiologies. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=39 SRC="FIGDIR/small/642628v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@16039e2org.highwire.dtl.DTLVardef@7865c3org.highwire.dtl.DTLVardef@60e886org.highwire.dtl.DTLVardef@41db90_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗
bioRxiv2022

Empagliflozin reduces renal lipotoxicity in experimental Alport syndrome

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are anti-hyperglycemic agents that prevent glucose reabsorption in proximal tubular cells. SGLT2i improves renal outcomes in both diabetic and non-diabetic patients, indicating it may have beneficial effects beyond glycemic control. Here, we demonstrate that SGLT2i affects energy metabolism and renal lipotoxicity in experimental Alport syndrome (AS). In vitro, we found that SGLT2 protein expression levels in human and mouse podocytes were similar to tubular cells. Newly established immortalized podocytes from Col4a3 knockout mice (AS podocytes) accumulate lipid droplets along with increased apoptosis when compared to wildtype podocytes. Treatment with SGLT2i empagliflozin reduces lipid droplet accumulation and apoptosis in AS podocytes. Empagliflozin inhibits the utilization of glucose/pyruvate as a metabolic substrate in AS podocytes. In vivo, we demonstrate that empagliflozin reduces albuminuria and prolongs the survival of AS mice. Empagliflozin-treated AS mice show decreased serum blood urea nitrogen and creatinine levels in association with reduced triglyceride and cholesterol ester content in kidney cortices when compared to AS mice. Lipid accumulation in kidney cortices correlates with the decline in renal function. In summary, empagliflozin reduces renal lipotoxicity and improves kidney function in experimental AS in association with the energy substrates switch from glucose to fatty acids in podocytes.

cell biology↗