What does this research mean for the field?

PLIN5 phosphorylation regulates mitochondria-lipid droplet coupling to control hepatic lipid flux, and enhancing these organelle contacts reduces lipotoxicity during nutrient stress. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to understand how hepatocytes manage increased dietary fatty acids and the role of PLIN5.

March 25, 2026Open Access

PLIN5 phosphorylation orchestrates mitochondria lipid-droplet coupling to control hepatic lipid flux and steatosis

Key Points

This research aims to understand how hepatocytes manage increased dietary fatty acids and the role of PLIN5.
Utilized single-cell tissue imaging and spatial proteomics to analyze lipid processing.
Compared mitochondrial and lipid droplet interactions under fasting and Western diet conditions.
Examined the impact of different PLIN5 variants on organelle contact formation.
Assessed the effect of the S155A variant on lipotoxicity in a Western diet context.
Fasting increased contacts between mitochondria and lipid droplets, while these were rare on a Western diet.
Overexpression of the S155A PLIN5 variant enhanced these contacts and increased lipid droplet size.
The S155E variant decreased contacts and resulted in smaller lipid droplets.
S155A overexpression in a Western diet context reduced lipotoxicity.

Abstract

Abstract Steatotic liver disease is common, yet the mechanisms by which hepatocytes cope with surges in dietary fatty acids remain unclear. Here we use single-cell tissue imaging (scPhenomics) and spatial proteomics to map lipid handling across dietary states. Fasting remodeled mitochondria and lipid droplets (LDs), increasing mitochondria–LD contacts, whereas contacts were infrequent in Western diet (WD)-fed male mice. Fasting also elevated perilipin-5 (PLIN5), a mediator of mitochondria-LD tethering. PLIN5 overexpression modulated contact formation in a phosphorylation-dependent manner: the S155A variant enhanced organelle contacts and LD expansion, whereas the S155E variant reduced contacts and yielded fewer, smaller LDs. Overexpression of the S155A variant in WD reduced lipotoxicity. These data reveal an adaptive organelle-interaction program that channels lipids during nutrient stress and is attenuated by an obesogenic diet. Our work establishes scPhenomics for spatially resolved cell-state analysis and identifies PLIN5 phosphorylation as a lever to tune hepatocyte lipid flux, suggesting therapeutic potential for targeting mitochondria–LD coupling.

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