<p>Functioning as a “powerhouse”, the liver adapts to the
metabolic needs of the body by maintaining a homeostatic balance. Prolactin
receptor (PRLR) has been found
to have a copious existence in the liver. Having established a well-defined role in both reproductive
and endocrine systems, the role of this transmembrane protein in hepatocytes is
yet to be elucidated. Due to its abundant nature, we hypothesized that PRLR is
required for maintaining hepatic homeostasis and plays a role in liver
diseases. To test this hypothesis, we defined two specific aims. The first was
to explore whether PRLR loss-of-function affects liver structure and function
in physiological conditions. The second was to determine whether PRLR is
associated with liver pathology. We deleted the <i>Prlr</i> gene specifically in hepatocytes using a virus-based approach
and evaluated liver function, transcriptome, and activities of downstream signaling
molecules. Due to the absence of PRLR, we found that the urea cycle was
disrupted, concomitant with excessive accumulation of urea in the blood; 133 genes exhibited
differential expression, largely associated with hepatocyte structure,
metabolism, and inflammation; and the activities of STAT3 and 5 were reduced. The
results signify that PRLR indeed plays a homeostatic role in the liver. We also
used <i>Prlr</i><sup>+/-</sup> mice to
assess whether the loss of one allele of the <i>Prlr</i> gene alters maternal hepatic adaptations to pregnancy. As a
result, in the pre-pregnancy state and during the first half of gestation, the
expression of maternal hepatic PRLR protein was reduced approximately by half
owing to <i>Prlr</i> insufficiency. However,
during the second half of pregnancy, we observed compensatory upregulation of
this molecule, leading to minimal
interference in
STAT 3 and 5 signaling and liver size. Contrary to a previous study in the
breast and ovary, our results suggest that one allele of <i>Prlr</i> may be sufficient for the maternal liver to respond to this physiological
stimulus (pregnancy). Furthermore, we examined the expression and activity of
PRLR in fatty as well as cholestatic livers. Using a high fat diet, we induced non-alcoholic
fatty liver disease (NAFLD).
Strikingly and for the first time, we discovered that the short isoform of PRLR
(PRLR-S) was completely inactivated in response to NAFLD, whereas the long isoform
remained unchanged. This finding strongly suggests the involvement of PRLR-S in
lipid metabolism. We also postulate that PRLR-L may be the major regulator of
STAT signaling in the liver, consistent with other reports. Lastly, we induced
extrahepatic cholestasis via bile duct ligation (BDL) in mice. As this liver
disease progressed, the expression of both isoforms of PRLR generally declined
and was surprisingly accompanied by increased STAT 3 and 5 activity. The data
suggests that PRLR participates in this disease progression, with a
disconnection between PRLR signaling and STAT proteins. Collectively, our preliminary
studies suggest that PRLR signaling is required to maintain liver homeostasis
and more prominently, is involved in liver diseases, especially NAFLD. These
findings lay a foundation for our future studies.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/15021918 |
| Date | 06 August 2021 |
| Creators | Jennifer Abla Yanum (11157624) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/THE_ROLE_OF_PROLACTIN_RECEPTOR_SIGNALING_IN_LIVER_HOMEOSTASIS_AND_DISEASE/15021918 |
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