Unavailability of liver triacylglycerol increases serum cholesterol concentration induced by dietary cholesterol in exogenously hypercholesterolemic (ExHC) rats

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Abstract

Background

Exogenously hypercholesterolemic (ExHC) rats develop hypercholesterolemia and low hepatic triacylglycerol (TAG) levels when dietary cholesterol is loaded. The responsible gene Smek2 was identified via linkage analysis using the original strain Sprague–Dawley (SD) rats. In this study, we compared SD and ExHC rats to investigate a relationship between hypercholesterolemia and the low hepatic TAG levels observed in ExHC rats.

Methods

Male 4-weeks-old ExHC and SD rats were fed a 1% cholesterol diet for 1 week. Serum and liver parameters were analyzed. Gene expression and enzyme activities related to TAG metabolism were also assessed.

Results

We reproducibly observed higher serum cholesterol and lower hepatic TAG levels in ExHC rats than in SD rats. Golgi apparatus in the livers of ExHC rats secreted β-very-low-density lipoprotein (β-VLDL) that had higher cholesterol ester (CE) and lower TAG content than those in the β-VLDL secreted by SD rats. Gene expression related to fatty acid and TAG synthesis in ExHC rats was lower than that in SD rats. Enzymatic activities for fatty acid synthesis were also relatively lower in ExHC rats. Moreover, the fatty acid composition of hepatic and serum CE in ExHC rats showed that these CEs were not modified after secretion from the liver despite the similar activities of serum lecithin-cholesterol acyltransferase (LCAT) in ExHC rats to those in SD rats.

Conclusions

Low production of liver TAG and secretion of CE-rich, TAG-poor β-VLDL without modification by LCAT in the circulation contributed to hypercholesterolemia induced by dietary cholesterol in ExHC rats.

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Most cited references 35

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Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma.

Diego Calvisi, Chunmei Wang, Coral Ho … (2011)

De novo lipogenesis is believed to be involved in oncogenesis. We investigated the role of aberrant lipid biosynthesis in the pathogenesis of human hepatocellular carcinoma (HCC). We evaluated expression of enzymes that regulate lipogenesis in human normal liver tissues and HCC and surrounding, nontumor, liver tissues from patients using real-time reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and biochemical assays. Effects of lipogenic enzymes on human HCC cell lines were evaluated using inhibitors and overexpression experiments. The lipogenic role of the proto-oncogene AKT was assessed in vitro and in vivo. In human liver samples, de novo lipogenesis was progressively induced from nontumorous liver tissue toward the HCC. Extent of aberrant lipogenesis correlated with clinical aggressiveness, activation of the AKT-mammalian target of rapamycin signaling pathway, and suppression of adenosine monophosphate-activated protein kinases. In HCC cell lines, the AKT-mammalian target of rapamycin complex 1-ribosomal protein S6 pathway promoted lipogenesis via transcriptional and post-transcriptional mechanisms that included inhibition of fatty acid synthase ubiquitination by the USP2a de-ubiquitinase and disruption of the SREBP1 and SREBP2 degradation complexes. Suppression of the genes adenosine triphosphate citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, or sterol regulatory element-binding protein 1, which are involved in lipogenesis, reduced proliferation, and survival of HCC cell lines and AKT-dependent cell proliferation. Overexpression of an activated form of AKT in livers of mice induced lipogenesis and tumor development. De novo lipogenesis has pathogenic and prognostic significance for HCC. Inhibitors of lipogenic signaling, including those that inhibit the AKT pathway, might be useful as therapeutics for patients with liver cancer. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans.

Stephen Turley, J Dietschy, D Spady (1993)

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The relationship between serum total cholesterol and all-cause or cause-specific mortality in a 17.3-year study of a Japanese cohort.

Tomonori Okamura, Akira Okayama, Takashi Kadowaki … (2006)

No study has shown a positive relationship between hypercholesterolemia and all-cause mortality in the Japanese population. Therefore, a cohort study of 17.3 years' duration was conducted on 9216 participants aged 30 years or older, selected randomly from throughout Japan. In both the lowest ( or=6.71mmol/L, 260mg/dl) total cholesterol (TC) groups, there was a positive association between TC and risk of all-cause mortality (hazard ratio (HR) 1.19; 95% confidence interval (CI), 1.03-1.37 and 1.36 (95% CI, 1.05-1.77), respectively). The lowest TC group had an increased risk of liver disease (HR 3.03; 95% CI, 1.70-5.43), whereas the highest TC group had an increased risk of coronary heart disease (HR 3.81; 95% CI, 1.70-5.43). After exclusion of deaths due to liver disease during the entire follow-up period and all-cause deaths within the first 5 years of follow-up, the increased HR in the lowest TC group disappeared (HR 1.05; 95% CI, 0.89-1.24). Although the cut-off point seemed to be higher than that for Western populations, hypercholesterolemia was shown to be positively associated with all-cause mortality in Japan.

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Author and article information

Journal

Journal ID (nlm-ta): Lipids Health Dis

Journal ID (iso-abbrev): Lipids Health Dis

Title: Lipids in Health and Disease

Publisher: BioMed Central

ISSN (Electronic): 1476-511X

Publication date Collection: 2014

Publication date (Electronic): 22 January 2014

Volume: 13

Page: 19

Affiliations

[1 ]Laboratory of Nutrition Chemistry, Division of Bioresource and Bioenvironmental Sciences, Graduate School, Kyushu University, 6-10-1 hakozaki, higashi-ku, Fukuoka 812-8581, Japan

Article

Publisher ID: 1476-511X-13-19

DOI: 10.1186/1476-511X-13-19

PMC ID: 3902423

PubMed ID: 24450544

SO-VID: 831a2d91-2f25-4c13-ae08-198f07f0d84f

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Unavailability of liver triacylglycerol increases serum cholesterol concentration induced by dietary cholesterol in exogenously hypercholesterolemic (ExHC) rats

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Abstract

Background

Methods

Results

Conclusions

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Karger: Oncology

Most cited references 35

Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma.

Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans.

The relationship between serum total cholesterol and all-cause or cause-specific mortality in a 17.3-year study of a Japanese cohort.

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