Journal of Pharmaceutical and Biomedical Analysis 195 (2021) 113851

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Journal of Pharmaceutical and Biomedical Analysis

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Lipidomic profiling reveals triacylglycerol accumulation in the liver

during pregnane X receptor activation-induced hepatomegaly
Yiming Jiang, Xinpeng Yao, Shicheng Fan, Yue Gao, Huizhen Zhang, Min Huang ∗ ,
Huichang Bi ∗
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China

a r t i c l e i n f o a b s t r a c t

Article history: Pregnane X receptor (PXR) is highly expressed in the liver and plays an integral role in the control of
Received 19 October 2020 xenobiotic and endobiotic metabolism to maintain homeostasis. We previously reported that activation
Received in revised form 7 December 2020 of PXR significantly induced liver enlargement. But the lipid profiling during PXR-induced hepatomegaly
Accepted 14 December 2020
remains unclear. This study aimed to characterize the effect of PXR activation on hepatic lipid homeo-
Available online 17 December 2020
stasis by lipidomics analysis. Mice were intraperitoneally administered with the typical mPXR agonist,
pregnenolone 16␣-carbonitrile (PCN, 100 mg/kg/d), for 5 days. Liver and serum were collected for further
Keywords:
analysis. The results confirmed that PXR activation can significantly induce liver enlargement. An obvi-
Pregnane X receptor
Hepatomegaly
ous hepatic lipid accumulation was observed in PCN-treated mice, as determined by H&E and Oil Red O
Lipidomics staining. Ultra-high performance liquid chromatography-Q Exactive Orbitrap high-resolution mass spec-
Triacylglycerol accumulation trometer (UHPLC-Q Exactive Orbitrap HRMS)-based lipidomics was performed to characterize the change
in lipid species. A total of 20 potential lipid biomarkers were significantly perturbed. The most signifi-
cant change was found in the triacylglycerol (TG), which constituted with the lower number of carbon
atoms and double bonds. Moreover, the mRNA expression levels showed that PCN-induced PXR activa-
tion significantly regulated the expression of genes involved in the uptake, synthesis and metabolism of
TG, which was consistent with increased TG levels. Collectively, these findings demonstrated that lipids
such as TG were significantly accumulated during PXR-induced hepatomegaly.
© 2020 Elsevier B.V. All rights reserved.

1. Introduction Lipids are crucial elements of cellular or subcellular membranes.

The primary biological functions of lipids are membrane matri-
The pregnane X receptor (PXR, NR1I2) was a xenobiotic-sensing ces, energy storage, component of signaling [5]. Lipids can be
nuclear receptor and mainly expressed in the liver and intestine [1]. divided into eight categories, including fatty acyls, glycerophos-
PXR modulates many drug metabolizing enzymes and membrane- pholipids, glycerolipids, polyketides, prenol lipids, saccharolipids,
bound drug transporters involved in xenobiotic metabolism and sphingolipids and sterol lipids, each of them containing distinct
detoxification [2], such as cytochrome P450s and p-glycoprotein classes and subclasses [6]. The liver is the crucial organ that metab-
(P-gp). PXR flexibly accepts multifarious ligands with significant olizes lipids to maintain energy homeostasis, which supplies the
structural differences, and the flexible and large receptor-binding main energy sources to the extra-hepatic tissues through keto-
site allowing a variety of ligands makes PXR a perfect regulator for genesis and oxidation [7]. Hepatic lipids are highly sensitive and
sensing changes with internal environment and homeostasis [3]. dynamic, and they are transformed constantly in pathological and
The PXR agonists are ubiquitous, including endogenous hormones, physiological environment. The balance of lipid metabolism is
dietary steroids, pharmaceutical agents, and xenobiotic chemicals fundamental for disease states and healthy homeostasis, and the
[4], which promote more potential of exposure the PXR activation. dysregulation of hepatic lipids is related to various diseases, such as
metabolic syndrome, fatty liver diseases, cardiovascular diseases,
and diabetes [8].
It has been reported that PXR plays an important role in lipid
∗ Corresponding authors at: School of Pharmaceutical Sciences, Sun Yat-sen Uni-
homeostasis via regulating the enzymes and transporters involved
versity, 132# Waihuandong Road, Guangzhou University City, Guangzhou 510006,
PR China.
in lipid synthesis and disposition [9]. Thus, the dynamic change of
E-mail addresses: huangmin@[Link] (M. Huang), lipids upon PXR activation, particularly the action of bioactive lipid
bihchang@[Link] (H. Bi).

[Link]
0731-7085/© 2020 Elsevier B.V. All rights reserved.
Y. Jiang, X. Yao, S. Fan et al. Journal of Pharmaceutical and Biomedical Analysis 195 (2021) 113851

composition, can provide a better understanding of the effect of 2.4. Biochemical evaluation
PXR on hepatic physiology and pathology. Lipidomics is currently
established as a powerful tool that provides rich information on Hepatic TG levels were measured using a triglyceride assay Kit
metabolic profiling of lipids. (Nanjing Jiancheng Bioengineering Institute, Nanjing, China).
We previously reported that activation of PXR significantly
induces liver enlargement [10]. But we found PXR activation 2.5. UHPLC-Q Exactive Orbitrap HRMS-based lipidomic analysis
induced lipid deposition, and the lipid profiling during PXR-induced
hepatomegaly remains unclear. Thus, this study aimed to explore Liver lipidomics analysis was performed according to our
the effect of PXR activation on hepatic lipid homeostasis in mice. previously reported protocol [11]. Briefly, homogenized liver sam-
First, we confirmed significant liver enlargement in response to ples were exacted with a mixture of MeOH/MTBE/H2 O ([Link],
PCN-induced PXR activation, and found PXR activation induced v/v/v, 12 mL total). After centrifuged, the organic phase (100 ␮L)
lipid accumulation. Further lipidomics analysis showed a total of 20 was removed and evaporated to dryness under nitrogen, evapo-
potential lipid biomarkers were significantly perturbed. The most rated extracts were dissolved in MeOH/IPA (1:1 v/v; 1 mL), and
significant change was found in the triacylglycerol (TG), which con- centrifuged to remove insoluble materials. A 2 ␮L aliquot of super-
stituted with the lower number of carbon atoms and double bonds. natant samples was injected into the UHPLC-Q Exactive system
Consistently, PXR activation significantly regulated the expression (Thermo Fisher Scientific, Waltham, MA). The chromatographic
of genes involved in the uptake, synthesis and metabolism of TG. separation and MS analysis were performed according to the pre-
These findings demonstrated that lipids such as TG was signifi- viously reported protocol.
cantly accumulated during PXR-induced hepatomegaly.
2.6. Lipid components identification and multivariate data
analysis
2. Material and methods
Mass spectral data was aligned and identified by using Lipid-
2.1. Animals Search (Thermo Fisher Scientific, Waltham, MA). The data matrix
was further analyzed using SIMCA-P + 13.0 (Umetrics, Kinnelon,
Eight- to nine-week-old male C57BL/6 mice weighing 20−22 NJ). Principle component analysis (PCA) was used to separate the
g were purchased from the Centre of Laboratory Animal Science PCN-treated group and the vehicle group. Orthogonal projections
of Guangdong (Foshan, China). The mice were randomly grouped to latent structures discriminant analysis (OPLS-DA) was used to
and i.p. injected with vehicle (corn oil, Sigma, St. Louis, MO) or 100 identify the major latent variables in the data matrix, and the
mg/kg/d PCN (Sigma, St. Louis, MO) for 5 days. Livers and bloods potential lipid components were analyzed the ions contributing to
were harvested at 12 h after the last injection. Blood samples were separation of the each groups in the S-plots. The ions with corre-
centrifuged at 3000 rpm for 15 min to collect serum for biochem- lation of 0.8 higher or -0.8 lower scores to the model were further
ical measurement. The liver was rapidly dissected and weighed, a identified.
portion of liver was immediately fixed in 10 % buffered formalin
for histological section. The remaining tissue was flash frozen in 2.7. Quantitative real-time PCR analysis
liquid nitrogen and stored at −80 ◦ C for further use. All animals
were housed in a specific pathogen-free environment with a 12 h Total RNA was isolated using Trizol reagent (Invitrogen, Grand
light/dark cycle, and all mice were fed with laboratory chow diet Island, NY, USA) and quantified by the NanoDrop spectrophotome-
(Guangdong Medical Laboratory Animal Center). All procedures ter (Thermo Scientific, Rockford, IL, USA) as described previously
were approved by the Sun Yat-Sen University Institutional Animal [10]. Complementary DNA was synthesized with 1 ␮g of total RNA
Care and Use Committee. using a PrimeScript RT reagent kit (TaKaRa Biotech, Kyoto, Japan).
SYBR Premix Ex Taq II kit (TaKaRa Biotech, Kyoto,Japan) was used
2.2. Western blot analysis to perform qRT-PCR mix. The amplification reaction was carried
out in the ABI-Prism 7500 sequence detection system (Applied
Western blot was performed as described in our previous Biosystems, Foster City, CA). Results were normalized to mouse 18S
report [10]. Rabbit polyclonal anti-CYP3A antibody was purchased mRNA. Gene-specific primers were obtained from a primer bank
from ABclonal Technology (ABclonal Tech, Wuhan, China). Mouse and sequences of primers were listed in Table S1.
monoclonal anti-P-gp antibody was acquired from Santa Cruz
Biotechnology (Santa Cruz, CA, USA). Rabbit polyclonal anti-GST␣ 2.8. Statistical analysis
antibody was purchased from Sangon Biotechnology (Sangon Tech,
Shanghai, China). Rabbit polyclonal anti-GAPDH antibody was The data were expressed as the means ± standard deviation
obtained from Cell Signaling Technology (Cell Signaling Technol- (SD). Unpaired Student’s t-test was used for statistical analysis of
ogy, MA, USA). data using GraphPad Prism 6 (GraphPad Software Inc, San Diego,
CA). P values less than 0.05 were considered significant. In lipidomic
analysis, the false discovery rate (FDR) q value was used to correct
2.3. Histological analysis for multiple comparisons, significant differential expression was
adjusted q < 0.05.
As for hematoxylin and eosin staining, liver tissues were fixed in
neutral buffered formalin and embedded in paraffin. Fixed tissues 3. Results
were cut into 4 ␮m thick sections and stained with hematoxylin and
eosin (H&E, Servicebio, Wuhan, China). H&E staining was pictured 3.1. PXR activation induces hepatomegaly and hepatic lipid
by Nikon Eclipse CI microscope (Nikon Instruments, Japan). deposition
As for Oil Red O staining, liver tissues were embedded in O.C.T.
Sections (10 ␮m) and then stained with Oil Red O (Sigma, St. Louis, After treated with PXR specific agonist PCN for 5 days, PXR
MO) to reveal lipid accumulation. Oil Red O staining was pictured downstream target proteins (CYP3A11, P-gp and GST␣) were sig-
by Nikon Eclipse CI microscope (Nikon Instruments, Japan). nificantly up-regulated (Fig. 1A), indicating mice liver PXR was

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Y. Jiang, X. Yao, S. Fan et al. Journal of Pharmaceutical and Biomedical Analysis 195 (2021) 113851

Fig. 1. Activation of PXR induces hepatomegaly and hepatic lipid accumulation. Mice were intraperitoneally injected with PCN (100 mg/kg/d) for 5 days. (A) Western blot was
used to measure PXR downstream protein expression. (B) Representative pictures of mice livers. (C) Liver weight. (D) Liver-to-body-weight ratio. ****P < 0.0001 compared
to the vehicle group. Data are expressed as mean ± SD (n = 6). (E) Liver histology was analysed by H&E staining. (F) Representative results of Oil Red O staining in the vehicle
and PCN-treated mice. Scale bar represents 100 ␮m.

activated. The liver weight and liver-to-body-weight ratio were tive modes, indicating distinct lipidomic profiles between the two
detected, as shown in Fig. 1B–C, significant liver enlargement and groups.
a significant increase of liver weight were observed in PCN-treated
group (1.34 ± 0.04 g) compared to the vehicle-treated group (0.99
± 0.01 g), and the liver-to-body-weight ratio was 33 % higher than 3.3. PXR activation induces TG accumulation
that of the vehicle mice (Fig. 1D).
Hepatic lipid deposition was monitored in each group using H&E In order to investigate the effect of PXR activation on the change
and Oil Red O staining. The vehicle group liver showed no lipid of lipids, OPLS-DA models were then developed to screen and
deposition and exhibited normal tissue morphology. Conversely, analyse lipid metabolites (Fig. 3A–B), and S-plots of the OPLS-DA
the PCN-treated mice had more developed hepatocyte balloon- models were showed the major ions contributing to the separa-
ing and proportions of lipid droplets in the liver (Fig. 1E). The tion (Fig. 3C,E). These potential lipid biomarkers were belonged
accumulation of hepatic lipid in the PCN-treated mice was con- to five different lipid classes, triacylglycerol (TG), phosphatidyl-
firmed by Oil Red O staining of liver sections (Fig. 1F). Thus, PXR choline (PC), phosphatidylethanolamine (PE), phosphatidylinositol
induced-lipid accumulation and hepatic steatosis were observed (PI) and phosphatidylserine (PS). The quantified lipids were dis-
in the PCN-treated mice. played in Fig. 3D and F, revealing that 18 lipid metabolites were
increased in the liver tissues of the PCN-treated group, includ-
ing TG (16:0/18:2/18:2), TG (16:0/18:1/18:2), TG (18:1/18:2/18:2),
3.2. Pattern analysis and lipidomic profiling TG (18:1/18:1/18:2), TG (18:2/18:2/18:2), TG (18:0/18:1/18:2),
TG (16:1/18:2/18:2), TG (16:0/18:2/18:3), TG (18:3/18:2/18:2),
UHPLC-Q Exactive Orbitrap HRMS data were used to com- TG (18:1/18:2/22:5), TG (18:2/17:1/18:2), TG (15:0/18:2/18:2), TG
pare the global lipid profiles of liver tissues. The chromatograms (16:0/18:2/21:5), PC (18:0/18:2), PC (18:0/22:6), PE(18:0/18:1), PS
obtained under positive and negative ionization modes were (18:0/21:0) and PI (18:0/18:2). Only the PC (16:0/16:1) and PE
presented in Fig. 2A–B. Total ion chromatography profiles sug- (16:0/20:4) showed lower levels in the PCN group than that of the
gested that the abundance of the PCN-treated group was higher vehicle group. Interestingly, the most significantly changed lipids
than those from the vehicle group, particularly during reten- were TG among these metabolites, which were increased in the
tion time of 14–18 min under positive mode. PCA approach PCN-treated mice. Furthermore, total acyl chain carbon numbers of
was then used to compare the differences in lipid composition TG was 51–54, and double bonds of TG was 3–7, suggesting these
between the vehicle-treated and PCN-treated groups. As shown TG had lower carbon number and double bond content. The hep-
in Fig. 2C–D, both the vehicle and PCN treatment group clustered atic TG were further determined. As shown in Fig. 3G, the level of
well and there was a clear separation under positive and nega- hepatic TG was increased to 2.53-fold of the vehicle mice.

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Y. Jiang, X. Yao, S. Fan et al. Journal of Pharmaceutical and Biomedical Analysis 195 (2021) 113851

Fig. 2. Multivariate statistical analysis based on the hepatic lipid metabolites. Mirror images of typical total ion chromatograms of UHPLC-Q Exactive Orbitrap HRMS under
(A) positive mode and (B) negative mode. PCA scores scatter plot of lipidomic profiles under (C) positive mode and (D) negative mode in the vehicle and PCN group mice. LPC,
lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; PA, phosphotidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PI,
phosphatidylinositol; PS, phosphatidylserine; SM, sphingomyelin; Cer, Ceramide; CL, cardiolipins and TG, triglycerides.

3.4. Effect of PXR activation on the expression of lipid considered potential drugs for digestive system disease including
homeostasis-related genes inflammatory bowel disease and drug-induced liver injury [17].
Clinically, the use of PXR agonists was cautioned due to adverse
We further measured the mRNA expression levels of those genes diet-drug or drug-drug interactions during therapeutic period [18].
involved in the process of hepatic TG uptake, synthesis, esterifica- Currently, novel strategies are supposed to separate the beneficial
tion, oxidation and export. As shown in Fig. 4, the mRNA levels effects of PXR from unwanted metabolic side effects. Moreover,
of gene encoding hepatic fatty acid binding protein 1 (Fabp1) and PXR activation and silencing promote steatosis of human hepatic
solute carrier family 13 member 5 (Slc13a5) were elevated to 1.46 cells by distinct lipogenic mechanisms [15]. Transgenic mice that
and 1.39-fold of the vehicle group after PCN treatment. The mRNA express the activated PXR (VP-PXR) showed hepatic steatosis with
levels of genes associated with TG synthesis such as squalene epox- increased liver TG levels [19]. On the other hand, activation of PXR
idase (Sqle), thyroid hormone-responsive spot 14 protein (Thrsp) by PCN results in a decrease in plasma LDL-cholesterol levels and
and elongation of very-long-chain fatty acids 6 (Elovl6) were sig- induction of hepatic steatosis in LDL receptor knockout mice [20].
nificantly increased to 2.43, 3.18 and 1.36-fold of the vehicle group. We previously reported that activation of PXR significantly induces
Furthermore, genes associated with ␤-oxidation and metabolism liver enlargement [10]. But the lipid profiling during PXR-induced
such as acetyl-CoA acyltransferase 2 (Acaa2) and Acyl-coenzyme A hepatomegaly remains unclear. Thus, this study aimed to explore
oxidase 1 (Acox1) were up-regulated to 2.31 and 2.15-fold of the the effect of PXR activation on hepatic lipid homeostasis in mice.
vehicle group after PCN treatment, respectively. In the current study, 811 ions were identified and 20 potential
hepatic lipid biomarkers were screened in the liver after the activa-
tion of PXR by PCN. These lipid biomarkers were mainly related to
4. Discussion TG, PC, PE, PI and PS metabolism, and the most remarkable change
was observed in TG. Liver is not served as the storage depot for
Many compounds can activate PXR, including endogenous lipid, so the steady state content of hepatic TG is low under phys-
steroids such as lithocholic acid and cholic acid [12]; several classes iological conditions. But PXR agonists can induce an imbalance of
of drug such as phenobarbital, phenytoin, amprenavir and nifedip- hepatic lipids resulting in the accumulation of TG. TG is the most
ine [3]; herbal remedies such as the St. John’s wort and Ginkgo important caloric source with respect to energy homeostasis. In
biloba [13]; and some dietary supplements such as vitamin E [14]. the early stage of liver regeneration, there is a transient steato-
In patients with fatty liver diseases, the PXR agonist rifampicin has sis characterized by the accumulation of TG, which are used as
been demonstrated to exacerbate symptoms [15], and suppression substrates for energy production and membrane synthesis [21].
of hepatic PXR activity was considered as one promising remedy for The study also showed that PXR activation induced accumulation
the ailment [16]. On the other hand, synthetic PXR agonists were

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Y. Jiang, X. Yao, S. Fan et al. Journal of Pharmaceutical and Biomedical Analysis 195 (2021) 113851

Fig. 3. Lipidomic analysis identifies altered hepatic lipid composition in the vehicle- and PCN-treated mice. OPLS-DA scores plots of hepatic lipid under positive mode (A)
and negative mode (B). Loadings S-plot of hepatic lipid under positive mode (C) and negative mode (E). The differentially expressed Lipid composition under (D) positive
mode and (F) negative mode. *FDR q < 0.05 compared to vehicle group. (G) liver TG content was measured after PCN treatment in mice. *P < 0.05 compared to the vehicle
group. Data are expressed as mean ± SD (n = 6).

of TG (16:0/18:2/18:2), TG (16:0/18:1/18:2), TG (18:1/18:2/18:2), Furthermore, the PXR-induced hepatic TG deposition directs

TG (18:1/18:1/18:2), TG (18:2/18:2/18:2), TG (18:0/18:1/18:2), TG our attention toward TG-specific mechanisms of PXR activation.
(16:1/18:2/18:2), TG (16:0/18:2/18:3), TG (18:3/18:2/18:2), TG TG is the most commonly circulated and stored energy, TG’s
(18:1/18:2/22:5), TG (18:2/17:1/18:2), TG (15:0/18:2/18:2), TG original sources include de novo lipogenesis, and intracellular
(16:0/18:2/21:5), and these TG contained lower number of car- TG stores. FABP1 and SLCL3A5 are important fatty acid trans-
bon atoms and double bonds. However, it was reported that TG porters in the liver. The prototypical PXR activator, rifampicin, can
with the lower number of carbon atoms and double bonds were markedly induced the mRNA and protein expression of SLC13A5,
associated with an increased risk of cardiovascular disease [22]. and knockdown of SLC13A5 expression is associated with reduced
Another study demonstrated that TG of relatively lower total acyl lipid accumulation [24]. Therefore, our results suggested that the
chain carbon number and double bond content (TG 50:0) and TG increased Fabp1 and Slc13a5 expression likely contributed to the
with relatively higher total acyl chain carbon number and double PCN-induced hepatic lipid deposition.
bond content (TG 58:10) captured integrating the positive and neg- PXR activation could also up-regulate the mRNA expression
ative factor, and these factor markers were altered up to 12 years of several key lipogenic genes including Sqle, Thrsp, and Elovl6,
prior to metabolic syndrome onset [23]. A substantial number of which play important roles in hepatic lipid biosynthesis. SQLE is
clinical drugs have the capacity to activate PXR, which may aggra- a member of flavoprotein monooxygenase family and located on
vate TG accumulation. For these reasons, a careful monitoring for the endoplasmic reticulum. SQLE catalyses the epoxidation of squa-
signs of progressive hepatic steatosis by PXR activation should be lene to generate 2,3-oxidosqualene, which is the first oxygenation
undertaken. step in the biosynthesis of sterols [25]. THRSP has been confirmed

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Y. Jiang, X. Yao, S. Fan et al. Journal of Pharmaceutical and Biomedical Analysis 195 (2021) 113851

Fig. 4. The effect of PXR activation on TG homeostasis-related gene expression. qRT-PCR analysis of Fabp1, Slc27a2, Slc13a5, Scarb, Acsl1, Akr1b10, Ppar, Scd1, Sqle, Thrsp,
Elovl6, Acaa2, Acly, Acox1, Cpt1a, Mttp, Srebf1 and Srebf2 expression levels in livers after PCN-treatment for 5 days in mice. *P < 0.05, **P < 0.01, ***P < 0.001 compared to the
vehicle group. Data are expressed as mean ± SD (n = 6).

for decades to regulate de novo lipogenesis, and its hepatic level Project administration, Funding acquisition, Writing - review &
is directly associated with the ability of liver to generate lipids. editing.
PXR might control Thrsp level through the direct repeat with 4-
bp spacer response element [26]. ELOVL6 is a member of the fatty Declaration of Competing Interest
acyl elongase family. It is responsible for the final step of endoge-
nous saturated fatty acid synthesis and involved in the formation The authors declare that there are no conflicts of interest.
of vaccenic acid and stearic acid [27].
The assembly of TG molecules constitutes the principal means
Acknowledgements
by which exported fatty acid and the liver stores [28]. TG may also
be used and expended in different ways. Here, PXR activation pro-
The work was supported by the Natural Science Foun-
moted the mRNA expression of Acaa2 and Acox1. ACAA2 is involved
dation of China (Grants: 81973392, 82025034, 82003840),
in lipid catabolism and acts as the vital enzyme for fatty acid ␤-
the National Key Research and Development Program (Grant:
oxidation [29], and ACOX1 is the first and the rate-limiting enzyme
2017YFE0109900), the Shenzhen Science and Technology Pro-
involved in peroxisomal ␤-oxidation of very long-chain fatty acids
gram (KQTD20190929174023858), the Natural Science Founda-
[30]. In contrast, previous study showed hepatic Acox-1 levels were
tion of Guangdong (Grant: 2017A030311018), the 111 project
markedly reduced in PXR-KO mice [31].
(Grant: B16047), the Key Laboratory Foundation of Guang-
dong Province (Grant: 2017B030314030), the Local Innovative
5. Conclusions and Research Teams Project of Guangdong Pearl River Talents
Program (2017BT01Y093), Guangdong Basic and Applied Basic
Therefore, the present study illustrated the effect of PXR on Research Foundation (Grant: 2019A1515010247), and the National
hepatic lipid homeostasis during PXR activation-induced hep- Engineering and Technology Research Center for New drug
atomegaly. PXR agonist PCN induces lipid deposition, which is Druggability Evaluation (Seed Program of Guangdong Province,
mainly attributed to the TG accumulation via regulating the genes 2017B090903004).
involved in the TG uptake, biosynthesis, and metabolism. The TG
constitutes with the lower number of carbon atoms and double Appendix A. Supplementary data
bonds, which might induce more lipidosis risks by exposure the
PXR agonists. These findings provide evidence of lipid accumulation Supplementary material related to this article can be found,
driven by PXR activation during PCN-induced liver enlargement, in the online version, at doi:[Link]
and provide new insights in the effect of PXR activation on lipid 113851.
homeostasis.
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