Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters

Dong, Bin; Young, Mark A.; Liu, Xueqing; Singh, Amar; Li, Jingwen

doi:10.1194/jlr.m070888

Cited by 29 publications

(38 citation statements)

References 50 publications

(64 reference statements)

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“…Compared to Sr-b1 KO mice, OCA treatment in WT mice did not change serum TG levels and reduced serum TC levels by 30.9% (p < .05) as compared to vehicle control (Figure 7a). This reduction was reflected by a decrease in the HDL-C fraction ( Figure 7c) consistent with literature reports (Dong, Young, Liu, Singh, & Liu, 2017;Webb et al, 2002;Yancey et al, 2000).…”

Section: Fxr Activation Substantially Reduced Serum Cholesterol Andsupporting

confidence: 91%

“…SR‐B1 has been known not only to mediate HDL‐C uptake but also to play key roles in transhepatic cholesterol excretion. Several studies have demonstrated the link between FXR‐mediated plasma cholesterol reduction and the increase in hepatic SR‐B1 expression (Dong et al, 2017; Hambruch et al, 2012). However, the mechanism underlying the effects of FXR activation on transhepatic cholesterol excretion has not been investigated in SR‐B1‐deficient mice under a normolipidemic state or hyperlipidemic conditions.…”

Section: Discussionmentioning

confidence: 99%

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FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR‐B1‐deficient mice fed a high‐fat and high‐cholesterol diet

et al. 2020

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Obeticholic acid (OCA) activates the farnesoid X receptor (FXR) to lower circulating total cholesterol (TC) and high density lipoprotein‐cholesterol (HDL‐C) concentrations and to stimulate fecal cholesterol excretion in mice by increasing hepatic SR‐B1 expression. Here we show that hepatic SR‐B1 depletion by an adenovirus expressing Sr‐b1 shRNA (Ad‐shSR‐B1) attenuated these beneficial effects of OCA in mice on a chow diet. The mRNA levels of ABC cholesterol transporter genes (Abca1, Abcg1, Abcg5, and Abcg8) were unchanged in the liver of hepatic SR‐B1‐depleted mice regardless of OCA treatment; however, a modest increase in Abca1, Abcg5, and Abcg8 mRNA levels was observed in the ileum of vehicle‐treated control mice and Abca1 and Abcg8 mRNA levels were increased more by OCA administration. OCA treatment of Sr‐b1 knock out (KO) mice (Sr‐b1‐/‐) fed a normal chow diet (NCD) displayed a similar lack of transhepatic cholesterol movement, as well as a modest increase in the levels of ileum cholesterol transporter expression. However, OCA treatment of Sr‐b1 KO mice fed a cholesterol‐enriched diet reduced circulating cholesterol and increased fecal cholesterol output to comparable degrees to that of wild‐type (WT) mice, and these effects were accompanied by substantial elevations of mRNA levels of Abca1, Abcg1, Abcg5, and Abcg8 in the ileum of Sr‐b1 KO mice. Our studies suggest that FXR activation stimulates intestinal cholesterol excretion and reduces diet‐induced hyperlipidemia through increased expression of ileal cholesterol transporters when hepatic SR‐B1‐mediated cholesterol movement is absent.

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Section: Fxr Activation Substantially Reduced Serum Cholesterol Andsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR‐B1‐deficient mice fed a high‐fat and high‐cholesterol diet

et al. 2020

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“…39 In hyperlipidemic hamsters, OCA treatment significantly reduced plasma HDL-cholesterol and promoted cholesterol efflux, but did not change triglyceride levels. 40 In the current study, we showed that treatment with OCA decreased serum triglyceride as well as 1-deoxysphingolipids levels to those seen in control mice fed a normal chow diet. It has been shown that 1-deoxysphingolipid levels are correlated with triglyceride levels, 19,31 and that elevated triglyceride levels in fact drive the increased formation of 1-deoxysphingolipids.…”

Section: Discussionsupporting

confidence: 56%

“…In LDL receptor (LDLR)‐/‐ mice, OCA treatment did not alter plasma total cholesterol levels . In hyperlipidemic hamsters, OCA treatment significantly reduced plasma HDL‐cholesterol and promoted cholesterol efflux, but did not change triglyceride levels . In the current study, we showed that treatment with OCA decreased serum triglyceride as well as 1‐deoxysphingolipids levels to those seen in control mice fed a normal chow diet.…”

Section: Discussionsupporting

confidence: 40%

Farnesoid X receptor activation induces the degradation of hepatotoxic 1‐deoxysphingolipids in non‐alcoholic fatty liver disease

Gai

Gui

Alecu

et al. 2020

Liver International

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Background & Aims Patients with non‐alcoholic fatty liver disease (NAFLD) exhibit higher levels of plasma 1‐deoxysphingolipids than healthy individuals. The aim of this study was to investigate the role of farnesoid X receptor (FXR) in 1‐deoxysphingolipid de novo synthesis and degradation. Methods Mice were fed with a high‐fat diet (HFD) to induce obesity and NAFLD, and then treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue. Sphingolipid patterns from NAFLD patients and mouse models were assessed by liquid chromatography‐mass spectrometry. The molecular mechanism underlying the effect of FXR activation on sphingolipid metabolism was studied in Huh7 cells and primary cultured hepatocytes, as well as in a 1‐deoxysphinganine‐treated mouse model. Results 1‐deoxysphingolipids were increased in both NAFLD patients and mouse models. FXR activation by OCA protected the liver against oxidative stress, apoptosis, and reduced 1‐deoxysphingolipid levels, both in a HFD‐induced mouse model of obesity and in 1‐deoxysphinganine‐treated mice. In vitro, FXR activation lowered intracellular 1‐deoxysphingolipid levels by inducing Cyp4f‐mediated degradation, but not by inhibiting de novo synthesis, thereby protecting hepatocytes against doxSA‐induced cytotoxicity, mitochondrial damage, and apoptosis. Overexpression of Cyp4f13 in cells was sufficient to ameliorate doxSA‐induced cytotoxicity. Treatment with the Cyp4f pan‐inhibitor HET0016 or FXR knock‐down fully abolished the protective effect of OCA, indicating that OCA‐mediated 1‐deoxysphingolipid degradation is FXR and Cyp4f dependent. Conclusions Our study identifies FXR‐Cyp4f as a novel regulatory pathway for 1‐deoxysphingolipid metabolism. FXR activation represents a promising therapeutic strategy for patients with metabolic syndrome and NAFLD.

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“…Fifty μl of serum samples obtained on day 11 after adenovirus injection from two animals of the same treatment group were pooled together, and a total of three pooled serum samples from Ad-shAcsl4 or Ad-shLacZ group were analyzed for cholesterol and TG levels of each of the major lipoprotein classes including chylomicron (CM, >80 nm), VLDL (30-80 nm), LDL (16-30 nm), and HDL (8-16 nm) with a dual detection HPLC system consisting of two tandem connected TSK gel Lipopropak XL columns (300 X 7.8-mm; Tosoh, Japan) at Skylight Biotech, Inc. (Tokyo, Japan) as described (9).…”

Section: Hplc Separation Of Serum Lipoprotein Cholesterol and Tgsmentioning

confidence: 99%

Liver-specific knockdown of long-chain acyl-CoA synthetase 4 reveals its key role in VLDL-TG metabolism and phospholipid synthesis in mice fed a high-fat diet

Singh

Kan

Kraemer

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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Long-chain acyl-CoA synthetase 4 (ACSL4) has a unique substrate specificity for arachidonic acid. Hepatic ACSL4 is coregulated with the phospholipid (PL)-remodeling enzyme lysophosphatidylcholine (LPC) acyltransferase 3 by peroxisome proliferator-activated receptor δ to modulate the plasma triglyceride (TG) metabolism. In this study, we investigated the acute effects of hepatic ACSL4 deficiency on lipid metabolism in adult mice fed a high-fat diet (HFD). Adenovirus-mediated expression of a mouse ACSL4 shRNA (Ad-shAcsl4) in the liver of HFD-fed mice led to a 43% reduction of hepatic arachidonoyl-CoA synthetase activity and a 53% decrease in ACSL4 protein levels compared with mice receiving control adenovirus (Ad-shLacZ). Attenuated ACSL4 expression resulted in a substantial decrease in circulating VLDL-TG levels without affecting plasma cholesterol. Lipidomics profiling revealed that knocking down ACSL4 altered liver PL compositions, with the greatest impact on accumulation of abundant LPC species (LPC 16:0 and LPC 18:0) and lysophosphatidylethanolamine (LPE) species (LPE 16:0 and LPE 18:0). In addition, fasting glucose and insulin levels were higher in Ad-shAcsl4-transduced mice versus control (Ad-shLacZ). Glucose tolerance testing further indicated an insulin-resistant phenotype upon knockdown of ACSL4. These results provide the first in vivo evidence that ACSL4 plays a role in plasma TG and glucose metabolism and hepatic PL synthesis of hyperlipidemic mice.

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Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters

Cited by 29 publications

References 50 publications

FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR‐B1‐deficient mice fed a high‐fat and high‐cholesterol diet

FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR‐B1‐deficient mice fed a high‐fat and high‐cholesterol diet

Farnesoid X receptor activation induces the degradation of hepatotoxic 1‐deoxysphingolipids in non‐alcoholic fatty liver disease

Liver-specific knockdown of long-chain acyl-CoA synthetase 4 reveals its key role in VLDL-TG metabolism and phospholipid synthesis in mice fed a high-fat diet

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