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<meta name="description" content="Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor responsible for regulating genes related to angiogenesis and metabolism. This study aims to explore the effect of a previously unreported mutation c.C2473T (p.R825S) in the C-terminal transactivation domain (CTAD) of HIF-2α that we detec …"><meta name="keywords" content="pmid:37453673, PMC10735172, doi:10.1016/j.phrs.2023.106851, Research Support, Non-U.S. Gov&#x27;t, Feiqiong Gao, Qigu Yao, Lanjuan Li, Animals, Basic Helix-Loop-Helix Transcription Factors / genetics, Basic Helix-Loop-Helix Transcription Factors / metabolism, Dyslipidemias* / genetics, Humans, Lipids, Liver Neoplasms*, Mice, Mutation, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta property="og:title" content="A novel HIF2A mutation causes dyslipidemia and promotes hepatic lipid accumulation - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/37453673/"><meta property="og:description" content="Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor responsible for regulating genes related to angiogenesis and metabolism. This study aims to explore the effect of a previously unreported mutation c.C2473T (p.R825S) in the C-terminal transactivation domain (CTAD) of HIF-2α that we detec …"><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="A novel HIF2A mutation causes dyslipidemia and promotes hepatic lipid accumulation - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/37453673/"><meta name="twitter:description" content="Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor responsible for regulating genes related to angiogenesis and metabolism. This study aims to explore the effect of a previously unreported mutation c.C2473T (p.R825S) in the C-terminal transactivation domain (CTAD) of HIF-2α that we detec …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">
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<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="7J9xtnDiZEJ2sx5G79rI7mEtxvw3fcQKowTC6d6EzfwwmYbwKs4KBua75zef8No4">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="7J9xtnDiZEJ2sx5G79rI7mEtxvw3fcQKowTC6d6EzfwwmYbwKs4KBua75zef8No4">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="7J9xtnDiZEJ2sx5G79rI7mEtxvw3fcQKowTC6d6EzfwwmYbwKs4KBua75zef8No4">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="7J9xtnDiZEJ2sx5G79rI7mEtxvw3fcQKowTC6d6EzfwwmYbwKs4KBua75zef8No4">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="7J9xtnDiZEJ2sx5G79rI7mEtxvw3fcQKowTC6d6EzfwwmYbwKs4KBua75zef8No4">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="37453673">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://linkinghub.elsevier.com/retrieve/pii/S1043-6618(23)00207-4"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3048&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=37453673&amp;db=pubmed&amp;nlmid=8907422"
title="See full text options at Elsevier Science"
data-ga-category="full_text"
data-ga-action="Elsevier Science"
data-ga-label="37453673"
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--linkinghub.elsevier.com-ihub-images-elsevieroa.png" alt="Elsevier Science full text link"><span class="text">
Elsevier Science
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/37453673/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=37453673&amp;db=pubmed&amp;nlmid=8907422"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="37453673"
><span class="text">
Free PMC article
</span></a>
</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/37453673/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/37453673/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="37453673" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F37453673%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="7J9xtnDiZEJ2sx5G79rI7mEtxvw3fcQKowTC6d6EzfwwmYbwKs4KBua75zef8No4"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="collections_button"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label">
Choose a collection:
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<h1 class="heading-title">
A novel HIF2A mutation causes dyslipidemia and promotes hepatic lipid accumulation
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A novel HIF2A mutation causes dyslipidemia and promotes hepatic lipid accumulation
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<span class="authors-list-item "><span class="full-name">Feiqiong Gao</span><span class="citation-separator">&nbsp;et al.</span></span>
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<span class="citation-year">2023 Aug</span><span class="citation-separator">.</span>
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data-ga-label="Feiqiong Gao">Feiqiong Gao</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; National Clinical Research Center for Infectious Diseases, Hangzhou City 310003, China." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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data-ga-label="Qigu Yao">Qigu Yao</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; National Clinical Research Center for Infectious Diseases, Hangzhou City 310003, China." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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data-ga-label="Wenyi Chen">Wenyi Chen</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; National Clinical Research Center for Infectious Diseases, Hangzhou City 310003, China." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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data-ga-label="Jiong Yu">Jiong Yu</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; National Clinical Research Center for Infectious Diseases, Hangzhou City 310003, China. Electronic address: yujiong@zju.edu.cn." href="#short-view-affiliation-4" ref="linksrc=author_aff">
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data-ga-label="Zhengping Zhuang">Zhengping Zhuang</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Building 37 Room 100, 37 Convent Drive, Bethesda, MD 20892, USA. Electronic address: zhengping.zhuang@nih.gov." href="#short-view-affiliation-5" ref="linksrc=author_aff">
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><sup class="key">1</sup> State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; National Clinical Research Center for Infectious Diseases, Hangzhou City 310003, China.</li>
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><sup class="key">4</sup> State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; National Clinical Research Center for Infectious Diseases, Hangzhou City 310003, China. Electronic address: yujiong@zju.edu.cn.</li>
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><sup class="key">5</sup> Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Building 37 Room 100, 37 Convent Drive, Bethesda, MD 20892, USA. Electronic address: zhengping.zhuang@nih.gov.</li>
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><sup class="key">6</sup> State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, 79 Qingchun Rd, Hangzhou City 310003, China; National Clinical Research Center for Infectious Diseases, Hangzhou City 310003, China. Electronic address: hccao@zju.edu.cn.</li>
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><sup class="key">7</sup> State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; National Clinical Research Center for Infectious Diseases, Hangzhou City 310003, China; Jinan Microecological Biomedicine Shandong Laboratory, Jinan City 250117, China.</li>
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Corrigendum to "A novel HIF2A mutation causes dyslipidemia and promotes hepatic lipid accumulation" [Pharmacol. Res. 194 (2023) 106851].
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<span class="docsum-authors full-authors">Gao F, Yao Q, Zhu J, Chen W, Feng X, Feng B, Wu J, Pacak K, Rosenblum J, Yu J, Zhuang Z, Cao H, Li L.</span>
<span class="docsum-authors short-authors">Gao F, et al.</span>
<span class="docsum-journal-citation full-journal-citation">Pharmacol Res. 2024 Apr;202:107135. doi: 10.1016/j.phrs.2024.107135. Epub 2024 Mar 8.</span>
<span class="docsum-journal-citation short-journal-citation">Pharmacol Res. 2024.</span>
<span class="citation-part">PMID: <span class="docsum-pmid">38461139</span></span>
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Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor responsible for regulating genes related to angiogenesis and metabolism. This study aims to explore the effect of a previously unreported mutation c.C2473T (p.R825S) in the C-terminal transactivation domain (CTAD) of HIF-2α that we detected in tissue of patients with liver disease. We sequenced available liver and matched blood samples obtained during partial liver resection or liver transplantation performed for clinical indications including hepatocellular carcinoma and liver failure. In tandem, we constructed cell lines and a transgenic mouse model bearing the corresponding identified mutation in HIF-2α from which we extracted primary hepatocytes. Lipid accumulation was evaluated in these cells and liver tissue from the mouse model using Oil Red O staining and biochemical measurements. We identified a mutation in the CTAD of HIF-2α (c.C2473T; p.R825S) in 5 of 356 liver samples obtained from patients with hepatopathy and dyslipidemia. We found that introduction of this mutation into the mouse model led to an elevated triglyceride level, lipid droplet accumulation in liver of the mutant mice and in their extracted primary hepatocytes, and increased transcription of genes related to hepatic fatty acid transport and synthesis in the mutant compared to the control groups. In mutant mice and cells, the protein levels of nuclear HIF-2α and its target perilipin-2 (PLIN2), a lipid droplet-related gene, were also elevated. Decreased lipophagy was observed in mutant groups. Our study defines a subpopulation of dyslipidemia that is caused by this HIF-2α mutation. This may have implications for personalized treatment.
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Keywords:
</strong>
Cholesterol (PubChem CID: 5997); Dexamethasone (PubChem CID: 5743); Hypoxia-inducible factor-2α; Lipid droplet; Lipophagy; Methanol (PubChem CID: 887); Mutation; Non-alcoholic fatty liver; Oleic Acid (PubChem CID: 445639); Palmitic Acid (PubChem CID: 985); Perilipin-2; Puromycin (PubChem CID: 439530); Streptomycin (PubChem CID: 19649).
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Declaration of Competing Interest The authors declare that they have no competing interests.</p>
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<div class="figure-caption-contents"><p> Sanger sequencing and peptide sequence.… </p></div>
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</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 1. </p>
</strong>
<div class="figure-caption-contents"><p> Sanger sequencing and peptide sequence. (A) 356 liver samples were obtained for Sanger… </p></div>
</div>
<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 1.
</strong>
<div class="figure-caption-contents">Sanger sequencing and peptide sequence. (A) 356 liver samples were obtained for Sanger sequencing and a point mutation in <i>HIF2A</i> was found in 5 patients. (B) Part of the <i>HIF2A</i> gene exon 16 sequencing results in 6 patients. One had no <i>HIF2A</i> mutation, while the other five patients carried a C2473T heterozygous mutation in exon 16 of <i>HIF2A</i> (arrow). (C) Comparison of polypeptide sequence was conducted. The mutant site was shown to be conserved across species (arrow).</div>
</figcaption>
</figure>
<figure class="figure-item "
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href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bf0/10735172/64c6ad13d6d2/nihms-1919843-f0002.jpg"
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aria-describedby="figure-caption-1"
role="button"
data-image-width="794"
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data-image-alt="Fig. 2."
data-pmc-id="PMC10735172"
data-figure-id="F2">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-1"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bf0/10735172/c6e98aa71c58/nihms-1919843-f0002.gif"
alt="Fig. 2." />
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<strong class="figure-label">
<p> Fig. 2. </p>
</strong>
<div class="figure-caption-contents"><p> HIF-2α <sup> mut </sup> mice model was… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 2. </p>
</strong>
<div class="figure-caption-contents"><p> HIF-2α <sup> mut </sup> mice model was established; the mutation resulted in fatty liver and… </p></div>
</div>
<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 2.
</strong>
<div class="figure-caption-contents">HIF-2α<sup>mut</sup> mice model was established; the mutation resulted in fatty liver and increased body weight in HIF-2α<sup>mut</sup> mice. (A) HIF-2α<sup>mut</sup> mice were constructed using targeted gene modification technology. (B-D) H&amp;E staining (B), Oil Red O staining (C) and general view (D) of mouse livers. HIF-2α<sup>mut</sup> mice and WT mice (control) were fed HFD and SCD, respectively. (E) Liver weight, body weight and liver weight/body weight ratio were compared between HIF-2α<sup>mut</sup> and WT mice with different treatments. (F) ALT and AST levels of four groups of mice. (G) Oil Red O staining results of primary hepatocytes. Primary hepatocytes were isolated from the livers of mutant and WT mice, respectively. The cells were then cultured in the Williams E supplemented with BSA or FFA. *<i>p</i>&lt;0.05, **<i>p</i>&lt;0.01, ***<i>p</i>&lt;0.001. WT: wild-type; HFD: high-fat diet; SCD: standard chow diet; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BSA: bull serum albumin; FFA: free fatty acids.</div>
</figcaption>
</figure>
<figure class="figure-item "
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itemprop="contentUrl"
aria-describedby="figure-caption-2"
role="button"
data-image-width="844"
data-image-height="1050"
data-image-alt="Fig. 3."
data-pmc-id="PMC10735172"
data-figure-id="F3">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-2"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bf0/10735172/2b45d3222de4/nihms-1919843-f0003.gif"
alt="Fig. 3." />
</a>
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<strong class="figure-label">
<p> Fig. 3. </p>
</strong>
<div class="figure-caption-contents"><p> HIF-2α <sup> mut </sup> was associated with… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 3. </p>
</strong>
<div class="figure-caption-contents"><p> HIF-2α <sup> mut </sup> was associated with lipid metabolism in SCD-fed mice. (A) OPLS-DA model… </p></div>
</div>
<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 3.
</strong>
<div class="figure-caption-contents">HIF-2α<sup>mut</sup> was associated with lipid metabolism in SCD-fed mice. (A) OPLS-DA model of lipid metabolites in the livers of WT and HIF-2α<sup>mut</sup> mice fed SCD. (B) The permutation test of the OPLS-DA model showed that Q<sup>2</sup>=0.873, R<sup>2</sup>X=0.616, R<sup>2</sup>Y=0.997, indicating that the model had good predictive ability. (C) Different classes of lipids were compared between SCD-fed WT and mutant mice by heatmap. The results demonstrated that the liver of mutant mice deposited more lipids than WT mice. (D) The fold change graph showed the top 20 differential lipids in HIF-2α<sup>mut</sup> mice compared to WT mice. Red represented up-regulation of lipid content and green represented down-regulation. (E and F) The relative levels of TG (E) and CE (F) for the two groups were presented as histograms. (G) KEGG pathway analysis of HIF-2α mutant mice unique to WT group. *<i>p</i>&lt;0.05, **<i>p</i>&lt;0.01, ***<i>p</i>&lt;0.001. SCD: standard chow diet; WT: wild-type; TG: triglyceride; CE: cholesteryl ester.</div>
</figcaption>
</figure>
<figure class="figure-item "
itemscope itemtype="http://schema.org/ImageObject"
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data-slide-index="3"
data-label-slug="fig-4">
<a class="figure-link"
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bf0/10735172/07f5698d4415/nihms-1919843-f0004.jpg"
itemprop="contentUrl"
aria-describedby="figure-caption-3"
role="button"
data-image-width="1050"
data-image-height="1046"
data-image-alt="Fig. 4."
data-pmc-id="PMC10735172"
data-figure-id="F4">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-3"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bf0/10735172/adc708f5cc8b/nihms-1919843-f0004.gif"
alt="Fig. 4." />
</a>
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<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
<div class="caption-wrap">
<strong class="figure-label">
<p> Fig. 4. </p>
</strong>
<div class="figure-caption-contents"><p> HIF-2α <sup> mut </sup> affected fatty acid… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 4. </p>
</strong>
<div class="figure-caption-contents"><p> HIF-2α <sup> mut </sup> affected fatty acid transport and synthesis, as well as lipid levels… </p></div>
</div>
<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 4.
</strong>
<div class="figure-caption-contents">HIF-2α<sup>mut</sup> affected fatty acid transport and synthesis, as well as lipid levels in vivo and in vitro. (A) mRNA levels of genes responsible for fatty acid transport and synthesis in mouse liver were detected by qRT-PCR. (B) Comparison of serum TG, TC and LDL-C in WT and mutant mice with different treatments. (C) Intrahepatic TG and TC levels of the four groups. (D) Intracellular TG and TC levels were tested in the primary hepatocytes. (E) mRNA levels of genes regulating fatty acid transport and synthesis were measured in four groups of primary hepatocytes. *<i>p</i>&lt;0.05, **<i>p</i>&lt;0.01, ***<i>p</i>&lt;0.001. qRT-PCR: quantitative Real-Time PCR; TG: triglyceride; TC: total cholesterol; LDL-C: low density lipoprotein cholesterol; WT: wild-type.</div>
</figcaption>
</figure>
<figure class="figure-item "
itemscope itemtype="http://schema.org/ImageObject"
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data-label-slug="fig-5">
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itemprop="contentUrl"
aria-describedby="figure-caption-4"
role="button"
data-image-width="849"
data-image-height="1050"
data-image-alt="Fig. 5."
data-pmc-id="PMC10735172"
data-figure-id="F5">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-4"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bf0/10735172/11eecd3f2fd1/nihms-1919843-f0005.gif"
alt="Fig. 5." />
</a>
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<div class="caption-wrap">
<strong class="figure-label">
<p> Fig. 5. </p>
</strong>
<div class="figure-caption-contents"><p> Cells lines with HIF-2α <sup> mut… </sup> </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 5. </p>
</strong>
<div class="figure-caption-contents"><p> Cells lines with HIF-2α <sup> mut </sup> were constructed and the mutation caused elevated lipid… </p></div>
</div>
<figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 5.
</strong>
<div class="figure-caption-contents">Cells lines with HIF-2α<sup>mut</sup> were constructed and the mutation caused elevated lipid accumulation. (A) Plasmids with HIF-2α and HIF-2α<sup>mut</sup> were constructed and packaged into lentiviruses. (B) HIF-2α mRNA levels in LO2 and HEK293 cells. LO2 and HEK293 cells were transfected with NC lentiviruses, lentiviruses with hHIF-2α, or lentiviruses with ΔhHIF-2α, and cultured in DMEM containing BSA or FFA, respectively. (C) Protein levels of flag in LO2 and HEK293 cells were assessed by western blot. (D and E) Intracellular TG and TC levels were measured in different treatment groups of LO2 cells (D) and HEK293 cells (E), respectively. (F and G) Oil Red O staining results of LO2 cells (F) and HEK293 cells (G) with different lentiviruses and treatments. *<i>p</i>&lt;0.05, **<i>p</i>&lt;0.01, ***<i>p</i>&lt;0.001 versus hHIF-2α group; <sup>###</sup><i>p</i>&lt;0.001 versus NC group. NC: negative control; BSA: bull serum albumin; FFA: free fatty acids.</div>
</figcaption>
</figure>
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data-label-slug="fig-6">
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itemprop="contentUrl"
aria-describedby="figure-caption-5"
role="button"
data-image-width="930"
data-image-height="1050"
data-image-alt="Fig. 6."
data-pmc-id="PMC10735172"
data-figure-id="F6">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-5"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bf0/10735172/f0a17f58db12/nihms-1919843-f0006.gif"
alt="Fig. 6." />
</a>
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<strong class="figure-label">
<p> Fig. 6. </p>
</strong>
<div class="figure-caption-contents"><p> The mutation increased HIF-2α protein… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 6. </p>
</strong>
<div class="figure-caption-contents"><p> The mutation increased HIF-2α protein levels in the nucleus. (A) HIF-2α and HIF-1α</p></div>
</div>
<figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 6.
</strong>
<div class="figure-caption-contents">The mutation increased HIF-2α protein levels in the nucleus. (A) HIF-2α and HIF-1α mRNA levels were assessed by qRT-PCR in WT and mutant mice fed HFD or SCD. (B) Total protein levels of HIF-2α were not significantly different between mutant and WT mice. Nuclear HIF-2α protein levels were elevated in the mutant group. (C) Immunohistochemistry of HIF-2α in mouse liver. HIF-2α<sup>mut</sup> groups had more stained HIF-2α protein. (D) mRNA levels of HIF-2α, HIF-1α, and the downstream targets of HIF-2α were assessed in primary hepatocytes. (E) Total protein levels of HIF-2α were similar between mutant and WT primary cells. Nuclear HIF-2α protein levels were elevated in the mutant group. (F) Western blot showed that the protein levels of nuclear HIF-2α were elevated in mutant HEK293 cells. (G) Co-immunoprecipitation was performed in SCD-fed HIF-2α<sup>mut</sup> and WT mice. HIF-2α could bind to HIF-1β, and mutant HIF-2α bound more HIF-1β. *<i>p</i>&lt;0.05, **<i>p</i>&lt;0.01, ***<i>p</i>&lt;0.001. qRT-PCR: quantitative Real-Time PCR; WT: wild-type; HFD: high-fat diet; SCD: standard chow diet.</div>
</figcaption>
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itemscope itemtype="http://schema.org/ImageObject"
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data-label-slug="fig-7">
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itemprop="contentUrl"
aria-describedby="figure-caption-6"
role="button"
data-image-width="812"
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data-pmc-id="PMC10735172"
data-figure-id="F7">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-6"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0bf0/10735172/d3907e4e1e1f/nihms-1919843-f0007.gif"
alt="Fig. 7." />
</a>
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<strong class="figure-label">
<p> Fig. 7. </p>
</strong>
<div class="figure-caption-contents"><p> PLIN2 protects lipid from lipophagy… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 7. </p>
</strong>
<div class="figure-caption-contents"><p> PLIN2 protects lipid from lipophagy in mutant groups. (A) PLIN2 mRNA levels were… </p></div>
</div>
<figcaption id="figure-caption-6" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 7.
</strong>
<div class="figure-caption-contents">PLIN2 protects lipid from lipophagy in mutant groups. (A) PLIN2 mRNA levels were compared in mice and primary hepatocytes, respectively. (B and C) Protein levels of HIF-2α, PLIN2, LC3, SQSTM1 were assessed in mice (B) and primary hepatocytes (C) by western blot. The mutation did not alter HIF-2α, but elevated PLIN2 and SQSTM1 protein levels and decreased LC3-II/I protein ratio. (D) mRNA levels of PLIN2 were elevated in mutant LO2 and HEK293 cells. Lipophagy-related genes expressed less in mutant HEK293 cells. (E) Primary hepatocytes isolated form mutant mice were as a control. After transfection of NC or PLIN2 siRNA, mRNA levels of <i>PLIN2</i>, <i>LC3</i>, <i>SQSTM1</i>, <i>BECLIN1</i> and <i>ATG5</i> in HIF-2α<sup>mut</sup> primary hepatocytes were determined by qRT-PCR. (F) Protein levels of PLIN2, LC3, SQSTM1 were measured in HIF-2α<sup>mut</sup> primary hepatocytes after transfection of PLIN2 siRNA. (G) Oil Red O staining of HIF-2α<sup>mut</sup> primary hepatocytes transfected with NC or PLIN2 siRNA and cultured in DMEM with FFA. PLIN2 siRNA reduced lipid accumulation in mutant primary cells. (H) PLIN2 protein levels in the liver of patients without HIF-2α<sup>mut</sup> (control) and patients with HIF-2α<sup>mut</sup> (patient 4 and 5). *<i>p</i>&lt;0.05, **<i>p</i>&lt;0.01, ***<i>p</i>&lt;0.001. qRT-PCR: quantitative Real-Time PCR; NC: negative control; FFA: free fatty acids.</div>
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