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Iqbal et al. Vessel Plus 2019;3:40 I http://dx.doi.org/10.20517/2574-1209.2019.28 Page 11 of 13

We observed that expression of genes involved in biosynthesis, efflux, and esterification of cholesterol was
down-regulated in Rorγ KO mice [Figure 3]. This may be the reason for less cholesterol levels in the livers
of these mice [Figure 2A]. Interestingly, we noticed a significant increase in the expression of Cyp7a gene,
which is responsible for the biosynthesis of bile acids in the liver. Although we do not know the exact
mechanism of how hepatic bile acid signaling was impaired in Rorγ KO, we speculate that a larger portion
of the hepatic cholesterol pool may be directed towards bile acid biosynthesis in the absence of RORγ.
[17]
Takeda et al. also observed an increase in the expression of Cyp7a gene in Rorγ KO mice fed a chow diet.
However, when these mice were fed a high fat diet for eight weeks, the levels of their liver, serum, and fecal
bile acid pools were reduced significantly. It is possible that the high fat diet is repressing the expression of
some other genes involved in the bile acid biosynthesis pathway.

In this study, we demonstrated that RORγ plays a significant role in the regulation of the expression of
lipid metabolism genes that are involved in lipid biosynthesis, storage, and fatty acid oxidation. Our data
also suggest that a cross-talk may occur between various transcription factors to maintain overall lipid
homeostasis in the body. Previously, it has been shown that hepatic circadian clock plays a critical role in
[17]
regulating major aspects of lipid metabolism through RORγ activity . In a different experimental setting,
we expanded the investigation to look at the changes in several lipid metabolism genes that were not
studied previously. We also looked at the expression of different transcription factors to study the cross-talk
between RORγ and these transcription factors to regulate lipid homeostasis. Most of the findings in this
current study are consistent and added substantive findings to the previously published reports [17,19] .

In summary, we show here that ablation of RORγ activity reduce lipid biosynthesis but enhance fatty acid
oxidation by modulating the expression of several lipid metabolism genes. However, this study has some
limitations because global RORγ-deficient mice are born healthy and fertile but die within the first four
[15]
months after birth due to high incidence of T-cell lymphomas in the thymus . Therefore, further studies are
warranted to show the effect of RORγ deficiency on lipid metabolism in liver-specific KO mice to avoid any
[17]
complications or confounding effects due to T-cell lymphomas. We will extend the studies of Takeda et al.
to investigate role of RORγ on lipid metabolism genes in chow-fed mice that were not studied previously. We
will also look at the expression of different transcription factors to study the cross-talk between these factors
and RORg to regulate lipid homeostasis. Furthermore, these mice may also be a good model to study the
effect of liver-specific Rorγ gene deletion on diet-induced obesity. In conclusion, it may be beneficial to
target RORγ activity for the management of obesity and related lipid metabolic disorders.

DECLARATIONS
Authors’ contributions
Conducted experiments: Jahangir Z, Veluru D, Otaibi AA, Mubarak SA, Subie BA, Alghanem AF
Contributed to the conception and design of the study: Iqbal J, Hawwari A, Bakillah A, Qarni AA
Performed data analysis and interpretation: Iqbal J, Bakillah A
Wrote the paper: Iqbal J, Bakillah A, Hawwari A

Availability of data and materials
All data and materials and mice are publicly available.

Financial support and sponsorship
This research was supported by National Science, Technology and Innovation Plan’s strategies technologies
program in Saudi Arabia (KACST: 10-BIO950-20) and an internal fund (RAC # 2083003) by KFSH&RC
to A.H. This work was also partially supported by the intramural grants RA16/024/A and RA17/013/A to
Iqbal J and RA17/014/A to Alghanem AF from KAIMRC. Jahangir Z worked on this study as a high school
summer trainee at KAIMRC.