The role of hepatic Surf4 in lipoprotein metabolism and the development of atherosclerosis in apoE−/− mice

Shen, Yishi; Gu, Hongmei; Zhai, Lei; Wang, Binxiang; Qin, Shucun; Zhang, Da Wei

doi:10.1016/j.bbalip.2022.159196

Cited by 19 publications

(21 citation statements)

References 47 publications

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“…Our data suggest that hepatic Surf4 could be similarly targeted, potentially achieving an even more profound reduction in plasma cholesterol without deleterious consequences. Indeed, it has been shown that inactivation of hepatic Surf4 is protective against diet-induced atherosclerosis in mice with PCSK9 overexpression ( Wang et al, 2021b ), LDLR deficiency ( Wang et al, 2021a ), and APOE deficiency ( Shen et al, 2022 ). Furthermore, polymorphism and mild reduction of SURF4 expression strongly associate with lower plasma lipid levels and reduced risks of cardiovascular disease in human populations ( Wang et al, 2021b ).…”

Section: Discussionmentioning

confidence: 99%

Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol

Tang

McCormick

et al. 2022

eLife

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PCSK9 negatively regulates low-density lipoprotein receptor (LDLR) abundance on the cell surface, leading to decreased hepatic clearance of LDL particles and increased levels of plasma cholesterol. We previously identified SURF4 as a cargo receptor that facilitates PCSK9 secretion in HEK293T cells (Emmer et al., 2018). Here, we generated hepatic SURF4-deficient mice (Surf4fl/fl Alb-Cre+) to investigate the physiologic role of SURF4 in vivo. Surf4fl/fl Alb-Cre+ mice exhibited normal viability, gross development, and fertility. Plasma PCSK9 levels were reduced by ~60% in Surf4fl/fl Alb-Cre+ mice, with a corresponding ~50% increase in steady state LDLR protein abundance in the liver, consistent with SURF4 functioning as a cargo receptor for PCSK9. Surprisingly, these mice exhibited a marked reduction in plasma cholesterol and triglyceride levels out of proportion to the partial increase in hepatic LDLR abundance. Detailed characterization of lipoprotein metabolism in these mice instead revealed a severe defect in hepatic lipoprotein secretion, consistent with prior reports of SURF4 also promoting the secretion of apolipoprotein B. Despite a small increase in liver mass and lipid content, histologic evaluation revealed no evidence of steatohepatitis or fibrosis in Surf4fl/fl Alb-Cre+ mice. Acute depletion of hepatic SURF4 by CRISPR/Cas9 or liver-targeted siRNA in adult mice confirms these findings. Together, these data support the physiologic significance of SURF4 in the hepatic secretion of PCSK9 and APOB-containing lipoproteins and its potential as a therapeutic target in atherosclerotic cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol

Tang

McCormick

et al. 2022

eLife

View full text Add to dashboard Cite

show abstract

“…Our data suggest that hepatic Surf4 could be similarly targeted, potentially achieving an even more profound reduction in plasma cholesterol without deleterious consequences. Indeed, it has been shown that inactivation of hepatic Surf4 is protective against diet-induced atherosclerosis in mice with PCSK9 overexpression (X. , LDLR deficiency (B. , and APOE deficiency (Shen et al, 2022). Furthermore, polymorphism and mild reduction of SURF4 expression strongly associate with lower plasma lipid levels and reduced risks of cardiovascular disease in human populations (X. .…”

Section: Discussionmentioning

confidence: 99%

Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol

Tang

McCormick

et al. 2022

Preprint

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PCSK9 negatively regulates low-density lipoprotein receptor (LDLR) abundance on the cell surface, leading to decreased hepatic clearance of LDL particles and increased levels of plasma cholesterol. We previously identified SURF4 as a cargo receptor that facilitates PCSK9 secretion in HEK293T cells (Emmer et al., 2018). Here, we generated hepatic SURF4-deficient mice (Surf4(fl/fl) Alb-Cre(+)) to investigate the physiologic role of SURF4 in vivo. Surf4(fl/fl) Alb-Cre(+) mice exhibited normal viability, gross development, and fertility. Plasma PCSK9 levels were reduced by ~60% in Surf4(fl/fl) Alb-Cre(+) mice, with a corresponding ~50% increase in steady state LDLR protein abundance in the liver, consistent with SURF4 functioning as a cargo receptor for PCSK9. Surprisingly, these mice exhibited a marked reduction in plasma cholesterol and triglyceride levels out of proportion to the partial increase in hepatic LDLR abundance. Detailed characterization of lipoprotein metabolism in these mice instead revealed a severe defect in hepatic lipoprotein secretion, consistent with prior reports of SURF4 also promoting the secretion of apolipoprotein B. Despite a small increase in liver mass and lipid content, histologic evaluation revealed no evidence of steatohepatitis or fibrosis in Surf4(fl/fl) Alb-Cre(+) mice. Acute depletion of hepatic SURF4 by CRISPR/Cas9 or liver-targeted siRNA in adult mice confirms these findings. Together, these data support the physiologic significance of SURF4 in the hepatic secretion of PCSK9 and APOB-containing lipoproteins and its potential as a therapeutic target in atherosclerotic cardiovascular diseases.

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“…For example, acute murine models fed only a Western diet display elevated serum TG and/or TC but without pronounced liver inflammation and fibrosis, which differs from human diseases, which are long-term consequences of an unhealthy lifestyle (21,22). Gene modification models such as db/db or ob/ob mice share some features with human diseases, but patients with these genetic alterations only account for a small proportion (23). Accordingly, we established a DIO mouse model with a long-term high-fat diet feeding period resembling patients with metabolic disorders who have no restriction on calorie intake and exhibit complications such as obesity, diabetes, dyslipidaemia, and NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Discovery of a novel, liver-targeted thyroid hormone receptor-β agonist, CS271011, in the treatment of lipid metabolism disorders

Lin

Huang

Deng³

et al. 2023

Front. Endocrinol.

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IntroductionThyroid hormone receptor β (THR-β) plays a critical role in metabolism regulation and has become an attractive target for treating lipid metabolism disorders in recent years. Thus, in this study, we discovered CS271011, a novel THR-β agonist, and assessed the safety and efficiency of CS271011 compared to MGL-3196 in vitro and in vivo. MethodsWe conducted luciferase reporter gene assays to assess the activation of THR-β and α in vitro. C57BL/6J mice were fed a high-fat diet for 12 weeks, CS271011 was administered by gavage at the dose of 1 mg/kg and 3 mg/kg, and MGL-3196 was administered at the dose of 3 mg/kg for 10 weeks. Body weight, food intake, serum and hepatic parameters, histological analysis, pharmacokinetic studies, RNA sequencing of the liver and heart, and expression of hepatic lipid-metabolic genes were determined to evaluate the safety and efficiency of CS271011. ResultsCompared with MGL-3196, CS271011 showed higher THR-β activation in vitro. In the diet-induced obesity mice model, CS271011 demonstrated favourable pharmacokinetic properties in mice and was enriched in the liver. Finally, CS271011 improved dyslipidaemia and reduced liver steatosis in the diet-induced obesity murine model. Mechanistically, CS271011 and MGL-3196 showed potent regulation of lipid metabolism-related genes. ConclusionsCS271011 is a potent and liver-targeted THR-β agonist for treating lipid metabolism disorders.

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The role of hepatic Surf4 in lipoprotein metabolism and the development of atherosclerosis in apoE−/− mice

Cited by 19 publications

References 47 publications

Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol

Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol

Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol

Discovery of a novel, liver-targeted thyroid hormone receptor-β agonist, CS271011, in the treatment of lipid metabolism disorders

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