6-Gingerol Regulates Hepatic Cholesterol Metabolism by Up-regulation of LDLR and Cholesterol Efflux-Related Genes in HepG2 Cells

Recent studies have revealed a novel route for cholesterol disposal through intestine known as transintestinal cholesterol efflux (TICE) that significantly contributes to fecal neutral sterol loss. This pathway is an integral part of reverse cholesterol transport (RCT), yet major mechanisms regulating TICE are not well understood. Using an unbiased transcriptional profiling approach in mouse models of augmented TICE, we found that hepatic expression of the enzyme Flavin monoxygenase 3 (FMO3) was dramatically repressed. At the same time we identified this enzyme through transcriptional profiling, it was reported that plasma levels of its product trimethylamineoxide (TMAO) are highly predictive of atheroslcerosis in humans, and TMAO is proatherogenic in mice. To further understand FMO3’s role as a regulator of cholesterol metabolism we used antisense oligonucleotides (ASO) to knockdown FMO3 expression in mouse liver in C57BL/6 mice fed either low (0.02%) or high (0.2%) levels of dietary cholesterol. As expected, FMO3 knockdown (>90% knockdown in the liver) increased the TMA/TMAO ratio in plasma more than 3-fold. Interestingly, knockdown of FMO biliary cholesterol levels were reduced by 60%, whereas fecal cholesterol loss was quite normal in FMO3 ASO treated mice fed a high cholesterol diet, which phenocopies a previously described mouse model where TICE predominates (NPC1L1-liver transgenic mice). ASO-mediated knockdown of FMO3 also unexpectedly reduced hepatic cholesteryl ester (CE) storage by 70% in mice fed 0.2% cholesterol. In parallel, knockdown of FMO3 reduces plasma VLDL cholesterol levels and the secretion rate of VLDL cholesteryl ester, but not triacylglycerol in cholesterol fed mice. FMO3 knockdown also reduced the hepatic expression of several liver X receptor (LXR) target genes, while increasing expression of genes involved in cholesterol synthesis. Collectively, these studies have identified FMO3 as a novel regulator of hepatic cholesterol metabolism and TICE. Given that plasma levels of FMO3’s product (TMAO) are strongly associated with atherosclerosis development in humans, and production of TMAO promotes atherosclerosis in mice, these studies have important implications for future cardiovascular drug discovery.

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The Effects of High Hydrostatic Pressure Extract of Mulberry Fruit on Hepatic Cholesterol Metabolism in Rats (P06-013-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.p06-013-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Jaerin Lee ◽

Soojin Lee ◽

Mak-Soon Lee ◽

Yoonjin Lee ◽

Jiyeon Kim ◽

...

Keyword(s):

Cholesterol Efflux ◽

Cholesterol Metabolism ◽

High Cholesterol Diet ◽

Atp Binding ◽

Mrna Levels ◽

Cholesterol Diet ◽

Hepatic Cholesterol ◽

High Cholesterol ◽

Mulberry Fruit ◽

Atp Binding Cassette

Abstract Objectives The objective of this study is to investigate the effects of high hydrostatic pressure (HHP) extract of mulberry fruit on the regulation of hepatic cholesterol metabolism in high-cholesterol diet fed rats. Methods Male Sprague-Dawley rats(6-week-old) were randomly divided into 5 groups, and fed with a normal diet (NOR), High cholesterol diet (HC), HC supplemented with 0.4% mulberry (ML) or 0.8% mulberry (MH) and HC treated with statin (ST) for 4 weeks. Results The HHP extract of mulberry fruit did not affect body weight gain and food intake and reduced the serum and liver lipids in the mulberry supplemented groups (ML, MH). In this study, we found that the HHP extract of mulberry fruit changed the level of genes involved in hepatic cholesterol metabolism. In the MH group, the mRNA levels of apolipoprotein A-1 (apoA-1), ATP-binding cassette transporter A1 (ABCA1) and lecithin-cholesterol acyltransferase (LCAT), which are involved in hepatic HDL biogenesis, were significantly increased by 1.80-, 1.77- and 2.65-fold, respectively, compared with the HC group. The MH group also significantly upregulated mRNA levels of cholesterol efflux related gene such as the liver X receptor α (LXRα), ATP-binding cassette protein G5 (ABCG5) and ATP-binding cassette protein G8 (ABCG8) compared to the HC group in the liver tissue. ABCG5 and ABCG8 expression levels of the MH group were also higher than those of the ST group. The mRNA level of cholesterol 7a-hydroxylase (CYP7A1), which is bile acid synthetic rate-limiting enzyme was higher in the MH group than that of the HC group. Furthermore, the immunohistochemical staining intensity became evident for CYP7A1 in liver of the MH group. Conclusions These results suggest at least partial involvement of HDL cholesterol synthesis, cholesterol efflux and bile acid synthesis in HHP extract of mulberry fruit mediated beneficial effects on hepatic cholesterol metabolism. Funding Sources None.

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Quercetin regulates hepatic cholesterol metabolism by promoting cholesterol-to-bile acid conversion and cholesterol efflux in rats

Nutrition Research ◽

10.1016/j.nutres.2015.11.019 ◽

2016 ◽

Vol 36 (3) ◽

pp. 271-279 ◽

Cited By ~ 23

Author(s):

Min Zhang ◽

Zongkai Xie ◽

Weina Gao ◽

Lingling Pu ◽

Jingyu Wei ◽

...

Keyword(s):

Bile Acid ◽

Cholesterol Efflux ◽

Cholesterol Metabolism ◽

Hepatic Cholesterol

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Regulation of rat hepatic cholesterol metabolism. Effects of lipoprotein composition on acyl coenzyme A:cholesterol acyltransferase in vivo and in the perfused liver and on hepatic cholesterol secretion

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)38636-3 ◽

1987 ◽

Vol 28 (8) ◽

pp. 930-940

Author(s):

P E Van Zuiden ◽

A D Cooper ◽

S K Erickson

Keyword(s):

Cholesterol Metabolism ◽

Perfused Liver ◽

Hepatic Cholesterol ◽

Lipoprotein Composition ◽

Cholesterol Secretion

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Hepatic cholesterol metabolism in cholesterol gallstone disease

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)42070-x ◽

1991 ◽

Vol 32 (3) ◽

pp. 469-475

Author(s):

E Reihnér ◽

B Angelin ◽

I Björkhem ◽

K Einarsson

Keyword(s):

Cholesterol Metabolism ◽

Cholesterol Gallstone ◽

Gallstone Disease ◽

Hepatic Cholesterol

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Hepatic cholesterol metabolism in normo- and hyperlipidemic patients with cholesterol gallstones.

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)40656-x ◽

1979 ◽

Vol 20 (1) ◽

pp. 107-115

Author(s):

J Ahlberg ◽

B Angelin ◽

I Björkhem ◽

K Einarsson ◽

B Leijd

Keyword(s):

Cholesterol Metabolism ◽

Hepatic Cholesterol ◽

Cholesterol Gallstones

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Effects of growth hormone on hepatic cholesterol metabolism. Lessons from studies in rats and humans

Growth Hormone & IGF Research ◽

10.1016/s1096-6374(99)80002-1 ◽

1999 ◽

Vol 9 ◽

pp. 1-7 ◽

Cited By ~ 9

Author(s):

M. Rudling ◽

P. Parini ◽

B. Angelin

Keyword(s):

Growth Hormone ◽

Cholesterol Metabolism ◽

Hepatic Cholesterol

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Short- and long-term effects of biliary drainage on hepatic cholesterol metabolism in the rat

Biochemical Journal ◽

10.1042/bj2690781 ◽

1990 ◽

Vol 269 (3) ◽

pp. 781-788 ◽

Cited By ~ 17

Author(s):

M J Smit ◽

A M Temmerman ◽

R Havinga ◽

F Kuipers ◽

R J Vonk

Keyword(s):

Bile Acid ◽

Bile Flow ◽

Cholesterol Metabolism ◽

Acid Output ◽

Biliary Secretion ◽

Surgical Trauma ◽

Hepatic Cholesterol ◽

Long Term Effects ◽

Short And Long Term

The present study concerns short- and long-term effects of interruption of the enterohepatic circulation (EHC) on hepatic cholesterol metabolism and biliary secretion in rats. For this purpose, we employed a technique that allows reversible interruption of the EHC, during normal feeding conditions, and excludes effects of anaesthesia and surgical trauma. [3H]Cholesteryl oleate-labelled human low-density lipoprotein (LDL) was injected intravenously in rats with (1) chronically (8 days) interrupted EHC, (2) interrupted EHC at the time of LDL injection and (3) intact EHC. During the first 3 h after interruption of the EHC, bile flow decreased to 50% and biliary bile acid, phospholipid and cholesterol secretion to 5%, 11% and 19% of their initial values respectively. After 8 days of bile diversion, biliary cholesterol output and bile flow were at that same level, but bile acid output was increased 2-3-fold and phospholipid output was about 2 times lower. The total amount of cholesterol in the liver decreased after interruption of the EHC, which was mainly due to a decrease in the amount of cholesteryl ester. Plasma disappearance of LDL was not affected by interruption of the EHC. Biliary secretion of LDL-derived radioactivity occurred 2-4 times faster in chronically interrupted rats as compared with the excretion immediately after interruption of the EHC. Radioactivity was mainly in the form of bile acids under both conditions. This study demonstrates the very rapid changes that occur in cholesterol metabolism and biliary lipid composition after interruption of the EHC. These changes must be taken into account in studies concerning hepatic metabolism of lipoprotein cholesterol and subsequent secretion into bile.

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