# An ER Stress Inducible START Domain Cholesterol Transport Protein, StarD5; and Unique Role in Fatty Liver Disease

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2024 · —

## Abstract

Fatty liver disease is an inflammatory response to accumulation of toxic metabolites within the
liver. In the United States, the progression of fatty liver disease to liver inflammation → fibrosis →
cirrhosis will soon be the leading cause of liver transplantation, especially within the Veteran’s
population; creating a challenge for our country’s Health Care budget. The molecular basis of
nonalcoholic fatty liver disease (NAFLD) is incompletely understood. Recent findings provide
strong evidence abnormal cholesterol metabolism drives the transition from fatty liver to
inflammation initiated by ER stress pathways. StarD5, a member of the StarD4 subfamily of
proteins that contains a characteristic START domain, is a soluble protein that binds and
translocates cholesterol within the cell. StarD5 is ‘upregulated’ by endoplasmic reticulum (ER)
stress, which makes it a candidate to play a key role in the carrying of cholesterol out of the ER
to maintain ER integrity. We have shown in preliminary observations shown that lack of StarD5
in hepatocytes can lead to a decrease in plasma membrane (PM) cholesterol and fluidity, an
increase in cholesterol and its potential inflammatory metabolites, a decrease in neutral lipid
(triglyceride) secretion, an increase in neutral lipid accumulation (triglycerides), subsequent
development of insulin resistance, and progression to steatohepatitis and ensuing transcriptional
activation of fibrotic pathways. Furthermore, the storing of higher levels of cholesterol and
triglycerides in StarD5-/- mouse livers, which is markedly exasperated with Western diet feeding,
leads to altered expression of cholesterol-regulated genes. Conversely, preliminary studies show
StarD5’s restoration in StarD5-/- livers, using an AAV9-StarD5 liver-selective overexpression
vector, is capable of reversing changes and protecting against ER stress. These observations
demonstrate an ‘adaptive protective role’ of StarD5 in NAFLD. Lipids, including cholesterol, have
been shown to be moved between membranes by non-vesicular lipid transfer proteins (LTP),
transfer that it is fueled by Phosphatidylinositols (PIPs). LTPs that target the ER have an FFAT
motif (diphenylalanine [FF] in an acidic tract [AT]) that interact with ER proteins. We have
identified a potential FFAT motif in the StarD5 protein that is conserved among species. In cells
transfected with the FFAT motif mutated, StarD5 does not interact with the PM, cells have less
accessible PM cholesterol, and, upon PIPs incubation, cells do not increase PM cholesterol as
they do in cells transfected with the WT StarD5. We hypothesize that StarD5 functions in the
physiologic maintenance of cholesterol homeostasis by moving cholesterol out of the ER. In
doing so, in cells with high or readily inducible levels of cholesterol, like hepatocytes, it prevents
accumulation of cholesterol and neutral lipids by moving cholesterol to the PM and potentiating
lipoprotein assembly and secretion. We propose to 1)...

## Key facts

- **NIH application ID:** 10692922
- **Project number:** 1I01BX005895-01A2
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** WILLIAM M PANDAK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10692922

## Citation

> US National Institutes of Health, RePORTER application 10692922, An ER Stress Inducible START Domain Cholesterol Transport Protein, StarD5; and Unique Role in Fatty Liver Disease (1I01BX005895-01A2). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10692922. Licensed CC0.

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