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. 2020 Oct 11;12(10):3088.
doi: 10.3390/nu12103088.

Endoplasmic Reticulum Stress Affects Cholesterol Homeostasis by Inhibiting LXRα Expression in Hepatocytes and Macrophages

Tian Wang  1 , Yiyang Zhao  1 , Zhongsheng You  1 , Xiatian Li  1 , Mingdi Xiong  1 , Hua Li  1 , Nianlong Yan  1
Affiliations

Endoplasmic Reticulum Stress Affects Cholesterol Homeostasis by Inhibiting LXRα Expression in Hepatocytes and Macrophages

Tian Wang et al. Nutrients. .

Abstract

Atherosclerosis (AS) is the most common cardiovascular disease, and reverse cholesterol transport (RCT) plays an important role in maintaining cholesterol homeostasis. Both endoplasmic reticulum (ER) stress and LXRα can affect the metabolism of cholesterol. However, whether ER stress can modulate cholesterol metabolism by LXRα in hepatocytes and macrophages remains unclear. Therefore, in this study, we aimed to explore the relationship between ER stress induced by tunicamycin and LXRα in hepatocytes and macrophages and clarify their possible mechanisms and roles in AS. C57BL/6 mice and Huh-7 and THP-1 cells were treated with tunicamycin and LXR-623 (an agonist of LXRα) alone or in combination. Tunicamycin-induced ER stress caused liver injury; promoted the accumulation of cholesterol and triglycerides; inhibited the expression of LXRα, ABCA1 and ABCG1 in the livers of mice, thus reducing serum high-density lipoprotein (HDL)-C, low-density lipoprotein (LDL)-C, total cholesterol and triglyceride levels; however, LXR-623 could attenuate ER stress and reverse these changes. We also obtained the same results in Huh-7 and THP-1 cells. ER stress induced by tunicamycin could clearly be reversed by activating LXRα because it promoted cholesterol efflux by enhancing the expression of ABCA1 and ABCG1 in hepatocytes and macrophages, contributing to attenuation of the development of AS.

Keywords: LXRα; atherosclerosis; cholesterol metabolism; endoplasmic reticulum stress; reverse cholesterol transport.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Tunicamycin-induced endoplasmic reticulum (ER) stress damaged hepatic function, and LXR-623 reversed this effect. Six-month-old mice were injected intraperitoneally with vehicle, 1 mg/kg tunicamycin and 15 mg/kg LXR-623. The livers were collected 48 h later. (A) Fresh liver morphology at harvest. (B) Expression levels of the ER stress indicator proteins CHOP and GRP78 in the liver. (C) Serum aspartate aminotransferase (AST) level. (D) Serum alanine aminotransferase (ALT) level. C, control; TM, tunicamycin; L, LXR-623; TM + L, tunicamycin + LXR-623. Data are shown as the mean ± SD (n = 6), ** p < 0.001 versus the C group. ## p < 0.001 versus the TM + L group.
Figure 2
Figure 2
Tunicamycin-induced ER stress caused liver lipid accumulation, and LXR-623 had the opposite effect. (A) Liver total cholesterol level. (B) Liver triglyceride level. (C) H&E staining of the liver. (D) Expression levels of HMGCR in the liver. C, control; TM, tunicamycin; L, LXR-623; TM + L, tunicamycin + LXR-623. Data are shown as the mean ± SD (n = 6), * p < 0.05 or ** p < 0.001 versus the C group. # p < 0.05 or ## p < 0.001 versus the TM + L group. & p < 0.05 versus L group.
Figure 3
Figure 3
LXR-623 inhibited the effect of ER stress on hepatic lipid efflux. (A) Serum triglyceride levels. (B) Serum total cholesterol level. (C) Serum high-density lipoprotein (HDL) cholesterol level. (D) Serum low-density lipoprotein (LDL) cholesterol level. (E) Expression levels of ABCA1, ABCG1 and LXRα in the liver. C, control; TM, tunicamycin; L, LXR-623; TM + L, tunicamycin + LXR-623. Data are shown as the mean ± SD (n = 6), * p < 0.05 or ** p < 0.001 versus the C group. ## p < 0.001 versus the TM + L group.
Figure 4
Figure 4
Tunicamycin-induced ER stress caused lipid accumulation in Huh-7 cells, and LXR-623 mitigated this effect. (A,B) Huh-7 cells were treated with various doses of tunicamycin (0, 0.1, 0.5, 1, 2, 4 μmol/L) and LXR-623 (0, 1, 3, 5, 7, 9 μmol/L). Expression levels of CHOP and GRP78 in Huh-7 cells. (C) Expression levels of CHOP and GRP78 in Huh-7 cells in 4 treatment groups. (D) Oil red O staining of Huh-7 cells. C, control; TM, tunicamycin; L, LXR-623; TM + L, tunicamycin + LXR-623. Data are shown as the mean ± SD (n = 3), * p < 0.05 or ** p < 0.001 versus the 0 or C group. ## p < 0.001 versus the TM + L group.
Figure 5
Figure 5
Tunicamycin-induced ER stress reduced cholesterol efflux in Huh-7 cells, and LXR-623 inhibited this effect. (A) Expression levels of HMGCR in Huh-7 cells. (B) Expression levels of ABCA1, ABCG1 and LXRα in Huh-7 cells. (C) Intracellular cholesterol measured by filipin staining. C, control; TM, tunicamycin; L, LXR-623; TM + L, tunicamycin + LXR-623. Data are shown as the mean ± SD (n = 3), * p < 0.05 or ** p < 0.001 versus the C group. # p < 0.05 or ## p < 0.001 versus the TM + L group.
Figure 6
Figure 6
Tunicamycin-induced ER stress caused lipid accumulation in THP-1 macrophages, and LXR-623 inhibited this effect. (A,B) THP-1 macrophages were treated with various doses of tunicamycin (0, 0.1, 0.25, 0.5, 1, 2 μmol/L) and LXR-623 (0, 1, 3, 5, 7, 9 μmol/L). Expression levels of CHOP and GRP78 in THP-1 macrophages. (C) Expression levels of CHOP and GRP78 in THP-1 macrophages in 4 different treatment groups. (D) Oil red O staining of THP-1 macrophages. C, control; TM, tunicamycin; L, LXR-623; TM + L, tunicamycin + LXR-623. Data are shown as the mean ± SD (n = 3), * p < 0.05 or ** p < 0.001 versus the 0 or C group. # p < 0.05 or ## p < 0.001 versus the TM + L group.
Figure 7
Figure 7
Tunicamycin-induced ER stress reduced cholesterol efflux in THP-1 macrophages, and LXR-623 inhibited this effect. (A) Expression levels of HMGCR in THP-1 macrophages. (B) Expression levels of ABCA1, ABCG1 and LXRα in THP-1 macrophages. (C) Filipin staining of THP-1 macrophages. C, control; TM, tunicamycin; L, LXR-623; TM + L, tunicamycin + LXR-623. Data are shown as the mean ± SD (n = 3), * p < 0.05 or ** p < 0.001 versus the C group. # p < 0.05 or ## p < 0.001 versus the TM + L group.
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