# The Role of Phosphatidylinositides in Lipid Metabolism

> **NIH NIH R01** · CHILDREN'S HOSPITAL & RES CTR AT OAKLAND · 2020 · $52,256

## Abstract

SUMMARY
As key directors of intracellular trafficking, phosphotidylinsotides (PIs) are a family of low abundance lipids that
impact almost every process within the eukaryotic cell. The low-density lipoprotein receptor (LDLR), a major
determinant of blood LDL levels, is the most efficacious therapeutic target for the prevention of cardiovascular
disease. Upon LDL binding, LDLR at the cell surface is internalized, where it releases the bound LDL and then
recycles back to the cell surface or is directed to the lysosome for degradation. Recently, we found that knock-
down of transmembrane protein 55B (TMEM55B), a phosphatidylinositol (4,5) bisphosphate [PI(4,5)P]
phosphatase, stimulated decay of LDLR protein in cells and raised plasma LDLC in mice. Since PI(4,5)P is
involved in lysosome formation, we hypothesize that PI(4,5)P phosphatases (such as TMEM55B) may alter
LDLC by regulating LDLR intracellular trafficking. We also found that reduction of PI(4,5)P phosphatases caused
severely impaired secretion of triglycerides into plasma. Notably, this occurred without the accumulation of liver
fat, and interestingly, was observed only in male mice, with no effect in females. The lack of hepatic fat
accumulation may be attributed to a number of different mechanisms including increased lipophagy (a process
of selective autophagy in which lipid droplets are targeted for lysosomal decay). PI(4,5)P is an important regulator
of lysosome reformation after autophagosome fusion, and we found that TMEM55B knock-down increased
lysosomes. These findings suggest that PI(4,5)P phosphatases may modulate hepatic TG secretion and storage
through a lysosome-dependent mechanism. Thus, the overall objective of this proposal is to evaluate the role of
PI(4,5)P in LDLR recycling and TG secretion. In Aim 1 we will i) Test if PI(4,5)P metabolizing enzymes impact
plasma LDL in the absence of LDLR using genetically modified mouse models; ii) Evaluate the effect of modifying
PI(4,5)P on Ldlr intracellular levels and localization in mouse hepatocytes; iii) Test if expression of enzymatically
inactive Tmem55b rescues the phenotypes observed in the Tmem55b knockout mouse; and iv) Evaluate if
PI(4,5)P phosphatase regulation of LDLR recycling is dependent on known regulators of LDLR decay. In Aim 2
we will i) Compare TG secretion in whole body versus liver-specific Tmem55b knockout male mice to confirm
that the defect is a hepatic mechanism; ii) Test if lack of hepatic fat accumulation, as would be expected to result
from impaired TG secretion, in hepatocytes from Tmem55b knockout mice is due to changes in fatty acid
oxidation, synthesis, or uptake, or TG synthesis; iii) Determine PI(4,5)P phosphatases depend on lysosome
and/or autophagosomes to impair TG secretion; and iv) Evaluate if the sex-specific effect of PI(4,5)P modulation
of TG secretion is due to the sex chromosome complement (XX vs. XY) and/or gonadal hormones. Investigation
of the role of PI(4,5)P in lipid and lipoprotein m...

## Key facts

- **NIH application ID:** 9838285
- **Project number:** 5R01HL139902-03
- **Recipient organization:** CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
- **Principal Investigator:** Marisa Medina
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $52,256
- **Award type:** 5
- **Project period:** 2018-01-15 → 2019-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838285

## Citation

> US National Institutes of Health, RePORTER application 9838285, The Role of Phosphatidylinositides in Lipid Metabolism (5R01HL139902-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9838285. Licensed CC0.

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