Expression of SREBP-1c Requires SREBP-2-mediated Generation of a Sterol Ligand for LXR in Livers of Mice

Rong, Shunxing; Cortés, Víctor; Rashid, Shahidur; Anderson, Norma N.; McDonald, Jeffrey G.; Liang, Guosheng; Moon, Young Ah; Hammer, Robert E.; Horton, Jay D.

doi:10.7554/elife.25015

Cited by 86 publications

(72 citation statements)

References 34 publications

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“…Critically, srebf1 is a key direct target of Lxrα (Schultz et al, 2000; Rong et al, 2017). Figure 5B shows that srebf1 and its two targets acaca and fasn were induced in nr1h3 −/− livers; while srebf2 and its target gene hmgcra were induced in Tg ( fabp2a:EGFP-nr1h3 ) livers.…”

Section: Resultsmentioning

confidence: 99%

Role of Intestinal LXRα in Regulating Post-prandial Lipid Excursion and Diet-Induced Hypercholesterolemia and Hepatic Lipid Accumulation

2017

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Post-prandial hyperlipidemia has emerged as a cardiovascular risk factor with limited therapeutic options. The Liver X receptors (Lxrs) are nuclear hormone receptors that regulate cholesterol elimination. Knowledge of their role in regulating the absorption and handling of dietary fats is incomplete. The purpose of this study was to determine the role of intestinal Lxrα in post-prandial intestinal lipid transport. Using Lxrα knockout (nr1h3−/−) and intestine-limited Lxrα over-expressing [Tg(fabp2a:EGFP-nr1h3)] zebrafish strains, we measured post-prandial lipid excursion with live imaging in larvae and physiological methods in adults. We also conducted a long-term high-cholesterol dietary challenge in adults to examine the chronic effect of modulating nr1h3 gene dose on the development of hypercholesterolemia and hepatic lipid accumulation. Over-expression of Lxrα in the intestine delays the transport of ingested lipids in larvae, while deletion of Lxrα increases the rate of lipid transport. Pre-treating wildtype larvae with the liver-sparing Lxr agonist hyodeoxycholic acid also delayed the rate of intestinal lipid transport in larvae. In adult males, deletion of Lxrα accelerates intestinal transport of ingested lipids. Adult females showed higher plasma Lipoprotein lipase (Lpl) activity compared to males, and lower post-gavage blood triacylglycerol (TAG) excursion. Despite the sexually dimorphic effect on acute intestinal lipid handling, Tg(fabp2a:EGFP-nr1h3) adults of both sexes are protected from high cholesterol diet (HCD)-induced hepatic lipid accumulation, while nr1h3−/− mutants are sensitive to the effects of HCD challenge. These data indicate that intestinal Lxr activity dampens the pace of intestinal lipid transport cell-autonomously. Selective activation of intestinal Lxrα holds therapeutic promise.

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Section: Resultsmentioning

confidence: 99%

Role of Intestinal LXRα in Regulating Post-prandial Lipid Excursion and Diet-Induced Hypercholesterolemia and Hepatic Lipid Accumulation

2017

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“…We strongly suspect that the higher plasma triglyceride levels in Gpihbp1 −/− mice during cold exposure were due to increased hepatic production of TRLs-simply because the release of fatty acids from adipose tissue during the cold would be expected to drive hepatic TRL production (30) and because TRL processing in Gpihbp1 −/− mice is defective (1). Of note, biomedical scientists often infer changes in TRL production when plasma triglyceride levels change after inhibiting LPL activity with Triton WR-1339 (31,32). LPL-mediated TRL processing is profoundly defective in Gpihbp1 −/− mice at baseline; hence, studies with Triton WR-1339 would make little sense.…”

Section: Resultsmentioning

confidence: 99%

“…Exposure to the cold stimulates lipolysis in adipose tissue (17)(18)(19), releasing fatty acids for the production of hepatic TRLs (which in the setting of GPIHBP1 deficiency cannot undergo normal processing). As noted earlier, biomedical scientists who study lipid metabolism in mice often infer changes in hepatic TRL production rates based on changes in plasma triglyceride levels when LPL activity is blocked (31,32). In Gpihbp1 −/− mice, we suspect that increased hepatic TRL production, combined with the block in TRL processing (2), explains the sharp increase in plasma triglyceride levels during cold exposure.…”

Section: Discussionmentioning

confidence: 99%

Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure

Larsson

Allan

Heizer

et al. 2018

Journal of Lipid Research

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Glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1), an endothelial cell protein, binds LPL in the subendothelial spaces and transports it to the capillary lumen. In Gpihbp1−/− mice, LPL remains stranded in the subendothelial spaces, causing hypertriglyceridemia, but how Gpihbp1−/− mice respond to metabolic stress (e.g., cold exposure) has never been studied. In wild-type mice, cold exposure increases LPL-mediated processing of triglyceride-rich lipoproteins (TRLs) in brown adipose tissue (BAT), providing fuel for thermogenesis and leading to lower plasma triglyceride levels. We suspected that defective TRL processing in Gpihbp1−/− mice might impair thermogenesis and blunt the fall in plasma triglyceride levels. Indeed, Gpihbp1−/− mice exhibited cold intolerance, but the effects on plasma triglyceride levels were paradoxical. Rather than falling, the plasma triglyceride levels increased sharply (from ∼4,000 to ∼15,000 mg/dl), likely because fatty acid release by peripheral tissues drives hepatic production of TRLs that cannot be processed. We predicted that the sharp increase in plasma triglyceride levels would not occur in Gpihbp1−/−Angptl4−/− mice, where LPL activity is higher and baseline plasma triglyceride levels are lower. Indeed, the plasma triglyceride levels in Gpihbp1−/−Angptl4−/− mice fell during cold exposure. Metabolic studies revealed increased levels of TRL processing in the BAT of Gpihbp1−/−Angptl4−/− mice.

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“…Antibodies: IgG-20B12 against hamster SREBP1 [10], IgG-7D4 against hamster SREBP2 [11], IgG-4H4 against Scap [12], anti-His tagged antibody (Millipore), donkey anti-mouse secondary IgG antibody (Jackson ImmunoResearch), and goat anti-rabbit secondary IgG antibody (Jackson ImmunoResearch).…”

Section: Methodsmentioning

confidence: 99%

Monitoring and Modulating Intracellular Cholesterol Trafficking Using ALOD4, a Cholesterol-Binding Protein

Endapally

Infante

Radhakrishnan

2019

Methods in Molecular Biology

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Mammalian cells carefully control their cholesterol levels by employing multiple feedback mechanisms to regulate synthesis of cholesterol and uptake of cholesterol from circulating lipoproteins. Most of a cell’s cholesterol (~80% of total) is in the plasma membrane (PM), but the protein machinery that regulates cellular cholesterol resides in the endoplasmic reticulum (ER) membrane, which contains a very small fraction (~1% of total) of a cell’s cholesterol. How does the ER communicate with PM to monitor cholesterol levels in that membrane? Here, we describe a tool, ALOD4, that helps us answer this question. ALOD4 traps cholesterol at the PM, leading to depletion of ER cholesterol without altering total cell cholesterol. The effects of ALOD4 are reversible. This tool has been used to show that the ER is able to continuously sample cholesterol from PM, providing ER with information about levels of PM cholesterol.

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Expression of SREBP-1c Requires SREBP-2-mediated Generation of a Sterol Ligand for LXR in Livers of Mice

Cited by 86 publications

References 34 publications

Role of Intestinal LXRα in Regulating Post-prandial Lipid Excursion and Diet-Induced Hypercholesterolemia and Hepatic Lipid Accumulation

Role of Intestinal LXRα in Regulating Post-prandial Lipid Excursion and Diet-Induced Hypercholesterolemia and Hepatic Lipid Accumulation

Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure

Monitoring and Modulating Intracellular Cholesterol Trafficking Using ALOD4, a Cholesterol-Binding Protein

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