# A central role of SEL1L-HRD1 ERAD in LPL maturation in adipocytes

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $389,215

## Abstract

A Central Role of SEL1L-HRD1 ERAD in LPL Maturation in Adipocytes
SUMMARY
My laboratory has a long-standing interest in protein folding and degradation within the endoplasmic reticulum
(ER) by defining the (patho-)physiological importance of mammalian ER quality-control machineries in vivo. ER-
associated degradation (ERAD) is the principal protein quality-control mechanism responsible for targeting
misfolded proteins in the ER for cytosolic proteasomal degradation. The SEL1L-HRD1 protein complex
represents the most conserved branch of ERAD from yeast to humans. We recently showed that SEL1L-HRD1
ERAD protein complex coordinates with autophagy, or specifically ER-phagy, in adipocytes to ensure the
maturation of lipoprotein lipases (LPL), a key enzyme involved in lipoprotein hydrolysis and systemic lipid
partitioning, in the ER. ERAD degrades misfolded nascent LPL in the ER and, when ERAD is impaired, LPL
forms aggregates and sequestered in ER fragments which are subsequently cleared by ER-phagy. When ERAD
and autophagy are both compromised, ER fragments containing LPL aggregates spatially coalesce into a distinct
cellular architecture termed Coalescence of ER Fragments (CERFs). Proteomics screens identify lipoprotein
lipase (LPL) and ER chaperone BiP as principal components of CERFs. Hence, our data point to a synergism
between ERAD and autophagy in adipocytes; however, the underlying molecular mechanism remains vague.
Our proteomics screens for SEL1L and LPL interactors both identified CCPG1, an ER-resident ER-phagy
receptor, as a top hit. Strikingly, our preliminary data showed that CCPG1 interacts with LPL and is an ERAD
substrate, i.e. degraded by SEL1L-HRD1 ERAD, suggesting that CCPG1 may link ERAD to ER-phagy of LPL
aggregates. Demonstrating the clinical relevance, we further showed that disease-causing LPL variants in
patients with familial hypertriglyceridemia are retained intracellularly as large aggregates in the absence of ERAD.
We will test the hypothesis that SEL1L-HRD1 ERAD regulates ER-phagy activity via ER-phagy receptor
CCPG1 to maintain ER homeostasis and ensure the maturation of secreted proteins such as LPL in
adipocytes. This model expands the current paradigm in ER biology by placing SEL1L-HRD1 ERAD at the
center of cellular quality-control function and identifying new LPL regulators. Using various mouse models, we
will (1) determine whether SEL1L-HRD1 ERAD regulates ER-phagy of LPL aggregates via CCPG1 in adipocytes;
and (2) delineate the pathological importance of SEL1L-HRD1 ERAD and CCPG1-mediated ER-phagy in the
pathogenicity of LPL disease mutants and its underlying mechanism. This study will provide unprecedented
insights into the role of various key ER quality control machineries in regulating LPL biology in adipocytes.
RELEVANCE TO HUMAN HEALTH: LPL deficiency is a rare genetic disorder that can lead to abnormal
accumulation of triglycerides in the blood and an increased risk of diabetes and cardiovascular disease. T...

## Key facts

- **NIH application ID:** 10773458
- **Project number:** 1R01DK137794-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Ling Qi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $389,215
- **Award type:** 1
- **Project period:** 2024-03-06 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10773458

## Citation

> US National Institutes of Health, RePORTER application 10773458, A central role of SEL1L-HRD1 ERAD in LPL maturation in adipocytes (1R01DK137794-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10773458. Licensed CC0.

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