TY  - JOUR
AU  - Šošić-Jurjević, Branka
AU  - Lütjohann, Dieter
AU  - Trifunović, Svetlana
AU  - Pavlović, Slađan
AU  - Borković-Mitić, Slavica
AU  - Jovanović, Ljubiša
AU  - Ristić, Nataša
AU  - Ljiljana, Marina
AU  - Ajdžanović, Vladimir
AU  - Filipović, Branko
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6120
AB  - Age and sex influence serum cholesterol levels, but the underlying mechanisms remain
unclear. To investigate further, we measured cholesterol, precursors (surrogate synthesis markers),
degradation products (oxysterols and bile acid precursors) in serum, the liver, jejunum, and ileum,
as well as serum plant sterols (intestinal absorption markers) in male and female Wistar rats (4 and
24 months old). The analysis of histomorphometric and oxidative stress parameters (superoxide
dismutase, catalase, glutathione-related enzyme activities, lipid peroxide, and protein carbonyl concentrations) in the liver and jejunum offered further insights into the age- and sex-related differences.
The hepatic gene expression analysis included AR, ERα, and sex-specific growth hormone-regulated
(Cyp2c11 and Cyp2c12) and thyroid-responsive (Dio1, Tbg, and Spot 14) genes by qPCR. We observed
age-related changes in both sexes, with greater prominence in females. Aged females had significantly
higher serum cholesterol (p < 0.05), jejunum cholesterol (p < 0.05), and serum plant sterols (p < 0.05).
They exhibited poorer hepato-intestinal health compared with males, which was characterized by
mild liver dysfunction (hydropic degeneration, increased serum ALT, p < 0.05, and decreased activity
of some antioxidant defense enzymes, p < 0.05), mononuclear inflammation in the jejunal lamina
propria, and age-related decreases in jejunal catalase and glutathione peroxidase activity (p < 0.05).
Aged females showed increased levels of 27-hydroxycholesterol (p < 0.05) and upregulated ERα gene
expression (p < 0.05) in the liver. Our study suggests that the more significant age-related increase in
serum cholesterol in females is associated with poorer hepato-intestinal health and increased jejunal
cholesterol absorption. The local increase in 27-hydroxycholesterol during aging might reduce the
hepatoprotective effects of endogenous estrogen in the female liver.
PB  - Basel: MDPI
T2  - International Journal of Molecular Sciences
T1  - Differences in Cholesterol Metabolism, Hepato-Intestinal Aging, and Hepatic Endocrine Milieu in Rats as Affected by the Sex and Age
IS  - 16
VL  - 24
DO  - 10.3390/ijms241612624
SP  - 12624
ER  - 

@article{
author = "Šošić-Jurjević, Branka and Lütjohann, Dieter and Trifunović, Svetlana and Pavlović, Slađan and Borković-Mitić, Slavica and Jovanović, Ljubiša and Ristić, Nataša and Ljiljana, Marina and Ajdžanović, Vladimir and Filipović, Branko",
year = "2023",
abstract = "Age and sex influence serum cholesterol levels, but the underlying mechanisms remain
unclear. To investigate further, we measured cholesterol, precursors (surrogate synthesis markers),
degradation products (oxysterols and bile acid precursors) in serum, the liver, jejunum, and ileum,
as well as serum plant sterols (intestinal absorption markers) in male and female Wistar rats (4 and
24 months old). The analysis of histomorphometric and oxidative stress parameters (superoxide
dismutase, catalase, glutathione-related enzyme activities, lipid peroxide, and protein carbonyl concentrations) in the liver and jejunum offered further insights into the age- and sex-related differences.
The hepatic gene expression analysis included AR, ERα, and sex-specific growth hormone-regulated
(Cyp2c11 and Cyp2c12) and thyroid-responsive (Dio1, Tbg, and Spot 14) genes by qPCR. We observed
age-related changes in both sexes, with greater prominence in females. Aged females had significantly
higher serum cholesterol (p < 0.05), jejunum cholesterol (p < 0.05), and serum plant sterols (p < 0.05).
They exhibited poorer hepato-intestinal health compared with males, which was characterized by
mild liver dysfunction (hydropic degeneration, increased serum ALT, p < 0.05, and decreased activity
of some antioxidant defense enzymes, p < 0.05), mononuclear inflammation in the jejunal lamina
propria, and age-related decreases in jejunal catalase and glutathione peroxidase activity (p < 0.05).
Aged females showed increased levels of 27-hydroxycholesterol (p < 0.05) and upregulated ERα gene
expression (p < 0.05) in the liver. Our study suggests that the more significant age-related increase in
serum cholesterol in females is associated with poorer hepato-intestinal health and increased jejunal
cholesterol absorption. The local increase in 27-hydroxycholesterol during aging might reduce the
hepatoprotective effects of endogenous estrogen in the female liver.",
publisher = "Basel: MDPI",
journal = "International Journal of Molecular Sciences",
title = "Differences in Cholesterol Metabolism, Hepato-Intestinal Aging, and Hepatic Endocrine Milieu in Rats as Affected by the Sex and Age",
number = "16",
volume = "24",
doi = "10.3390/ijms241612624",
pages = "12624"
}

Šošić-Jurjević, B., Lütjohann, D., Trifunović, S., Pavlović, S., Borković-Mitić, S., Jovanović, L., Ristić, N., Ljiljana, M., Ajdžanović, V.,& Filipović, B.. (2023). Differences in Cholesterol Metabolism, Hepato-Intestinal Aging, and Hepatic Endocrine Milieu in Rats as Affected by the Sex and Age. in International Journal of Molecular Sciences
Basel: MDPI., 24(16), 12624.
https://doi.org/10.3390/ijms241612624

Šošić-Jurjević B, Lütjohann D, Trifunović S, Pavlović S, Borković-Mitić S, Jovanović L, Ristić N, Ljiljana M, Ajdžanović V, Filipović B. Differences in Cholesterol Metabolism, Hepato-Intestinal Aging, and Hepatic Endocrine Milieu in Rats as Affected by the Sex and Age. in International Journal of Molecular Sciences. 2023;24(16):12624.
doi:10.3390/ijms241612624 .

Šošić-Jurjević, Branka, Lütjohann, Dieter, Trifunović, Svetlana, Pavlović, Slađan, Borković-Mitić, Slavica, Jovanović, Ljubiša, Ristić, Nataša, Ljiljana, Marina, Ajdžanović, Vladimir, Filipović, Branko, "Differences in Cholesterol Metabolism, Hepato-Intestinal Aging, and Hepatic Endocrine Milieu in Rats as Affected by the Sex and Age" in International Journal of Molecular Sciences, 24, no. 16 (2023):12624,
https://doi.org/10.3390/ijms241612624 . .

TY  - CONF
AU  - Šošić-Jurjević, Branka 
AU  - Jovanović, Ljubiša
AU  - Marina, Ljiljana
AU  - Ristić, Nataša
AU  - Miler, Marko
AU  - Ajdžanović, Vladimir
AU  - Filipović, Branko
AU  - Luetjohann, Dieter
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4975
AB  - The cholesterol oxidation product 27-hydroxycholesterol (27OHC) is enzymatically
produced from cholesterol by CYP27A1 in an alternative pathway of
cholesterol degradation to bile acids. This oxysterol also acts as an endogenous
selective estrogen receptor modulator (SERM). In healthy humans its
concentration in circulation increases in hypercholesterolemia and with age,
and is associated with increased risk of atherosclerosis, cardiovascular diseases
and breast cancer. Several drugs with SERM activity used for treatments of breast
cancer or osteoporosis have been reported to have sporadic hepatotoxic effects.
Women suffer from some liver diseases more commonly (acute liver failure,
autoimmune hepatitis, benign liver lesions, or primary biliary cirrhosis). For all of
these the incidence increases with advancing age. To the best of our knowledge,
there is no information in the literature, clinical or experimental, relating changes
in hepatic 27OHC with incidence of liver disease in the context of aging and sex.
To address this problem, we examined the effect of age and sex on liver and serum
concentrations of 27OHC, as well as the immunostaining pattern of CYP27A1 in
the liver of four-month and 24-month-old Wistar rats (experiments were repeated
twice with similar results, nZ5-6 animals/group) using LC MS/MS and
immunohistochemistry, respectively. Furthermore, we examined changes in
total cholesterol and concentration in liver and serum, liver histopathology, as
well as serum concentration of hepatic enzymes, alanine (ALT) and aspartate
aminotransferase (AST). The effect of age (P!0.05) on increase of serum and
hepatic 27OHC was obtained both in males and females (P!0.05) and followed
the same pattern of age-related total cholesterol increase (P!0.05). However, the
intrahepatic increase of 27OHC was dramatically more pronounced only in oldaged
females (P!0.0001). CYP27A1 immunostaining intensity was similar in all
experimental groups, being the strongest in the cytoplasm of centrilobular
hepatocytes, but the immunopositivity was diffusely spread throughout the liver
lobule. Histopathological analysis revealed age-related hepatocellular degeneration
(swelling and hydropic degeneration, increased fraction of binuclear
hepatocytes and focal fatty changes) only in females. Moreover, age-related
elevation of alanine transaminase (ALT) was observed only in female rats (P!
0.01). In conclusion, the obtained results confirmed age-related female-specific
increase of hepatic 27OHC as well as hepatocyte degeneration obsereved only in
the liver of rat females. These age-related adaptive changes in cholesterol
metabolism may atenuate hepatoprotective estrogen-like effects in the liver.
PB  - bioscientifica
C3  - 24th European Congress of  Endocrinology 2022; 21–24 May 2022; Milan, Italy
T1  - Is age-related hepatic elevation of endogenous SERM 27-hydroxycho lesterol associated with hepatocellular degeneration female-specific? - Results from Rat study?
DO  - 10.1530/endoabs.81.P615
SP  - P615
ER  - 

@conference{
author = "Šošić-Jurjević, Branka  and Jovanović, Ljubiša and Marina, Ljiljana and Ristić, Nataša and Miler, Marko and Ajdžanović, Vladimir and Filipović, Branko and Luetjohann, Dieter",
year = "2022",
abstract = "The cholesterol oxidation product 27-hydroxycholesterol (27OHC) is enzymatically
produced from cholesterol by CYP27A1 in an alternative pathway of
cholesterol degradation to bile acids. This oxysterol also acts as an endogenous
selective estrogen receptor modulator (SERM). In healthy humans its
concentration in circulation increases in hypercholesterolemia and with age,
and is associated with increased risk of atherosclerosis, cardiovascular diseases
and breast cancer. Several drugs with SERM activity used for treatments of breast
cancer or osteoporosis have been reported to have sporadic hepatotoxic effects.
Women suffer from some liver diseases more commonly (acute liver failure,
autoimmune hepatitis, benign liver lesions, or primary biliary cirrhosis). For all of
these the incidence increases with advancing age. To the best of our knowledge,
there is no information in the literature, clinical or experimental, relating changes
in hepatic 27OHC with incidence of liver disease in the context of aging and sex.
To address this problem, we examined the effect of age and sex on liver and serum
concentrations of 27OHC, as well as the immunostaining pattern of CYP27A1 in
the liver of four-month and 24-month-old Wistar rats (experiments were repeated
twice with similar results, nZ5-6 animals/group) using LC MS/MS and
immunohistochemistry, respectively. Furthermore, we examined changes in
total cholesterol and concentration in liver and serum, liver histopathology, as
well as serum concentration of hepatic enzymes, alanine (ALT) and aspartate
aminotransferase (AST). The effect of age (P!0.05) on increase of serum and
hepatic 27OHC was obtained both in males and females (P!0.05) and followed
the same pattern of age-related total cholesterol increase (P!0.05). However, the
intrahepatic increase of 27OHC was dramatically more pronounced only in oldaged
females (P!0.0001). CYP27A1 immunostaining intensity was similar in all
experimental groups, being the strongest in the cytoplasm of centrilobular
hepatocytes, but the immunopositivity was diffusely spread throughout the liver
lobule. Histopathological analysis revealed age-related hepatocellular degeneration
(swelling and hydropic degeneration, increased fraction of binuclear
hepatocytes and focal fatty changes) only in females. Moreover, age-related
elevation of alanine transaminase (ALT) was observed only in female rats (P!
0.01). In conclusion, the obtained results confirmed age-related female-specific
increase of hepatic 27OHC as well as hepatocyte degeneration obsereved only in
the liver of rat females. These age-related adaptive changes in cholesterol
metabolism may atenuate hepatoprotective estrogen-like effects in the liver.",
publisher = "bioscientifica",
journal = "24th European Congress of  Endocrinology 2022; 21–24 May 2022; Milan, Italy",
title = "Is age-related hepatic elevation of endogenous SERM 27-hydroxycho lesterol associated with hepatocellular degeneration female-specific? - Results from Rat study?",
doi = "10.1530/endoabs.81.P615",
pages = "P615"
}

Šošić-Jurjević, B., Jovanović, L., Marina, L., Ristić, N., Miler, M., Ajdžanović, V., Filipović, B.,& Luetjohann, D.. (2022). Is age-related hepatic elevation of endogenous SERM 27-hydroxycho lesterol associated with hepatocellular degeneration female-specific? - Results from Rat study?. in 24th European Congress of  Endocrinology 2022; 21–24 May 2022; Milan, Italy
bioscientifica., P615.
https://doi.org/10.1530/endoabs.81.P615

Šošić-Jurjević B, Jovanović L, Marina L, Ristić N, Miler M, Ajdžanović V, Filipović B, Luetjohann D. Is age-related hepatic elevation of endogenous SERM 27-hydroxycho lesterol associated with hepatocellular degeneration female-specific? - Results from Rat study?. in 24th European Congress of  Endocrinology 2022; 21–24 May 2022; Milan, Italy. 2022;:P615.
doi:10.1530/endoabs.81.P615 .

Šošić-Jurjević, Branka , Jovanović, Ljubiša, Marina, Ljiljana, Ristić, Nataša, Miler, Marko, Ajdžanović, Vladimir, Filipović, Branko, Luetjohann, Dieter, "Is age-related hepatic elevation of endogenous SERM 27-hydroxycho lesterol associated with hepatocellular degeneration female-specific? - Results from Rat study?" in 24th European Congress of  Endocrinology 2022; 21–24 May 2022; Milan, Italy (2022):P615,
https://doi.org/10.1530/endoabs.81.P615 . .