γ-Secretase Inhibition Lowers Plasma Triglyceride-Rich Lipoproteins by Stabilizing the LDL Receptor

Kim, KyeongJin; Goldberg, Ira J.; Graham, Mark; Sundaram, Meenakshi; Bertaggia, Enrico; Lee, Samuel X.; Li, Qiang; Haeusler, Rebecca A.; Metzger, Daniel; Chambon, Pierre; Yao, Zemin; Ginsberg, Henry N.; Pajvani, Utpal B.

doi:10.1016/j.cmet.2018.02.010

Cited by 19 publications

(14 citation statements)

References 80 publications

(93 reference statements)

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“…Other scholars found that LDLR‐deficient mice had increased secretion of VLDL and TG in the livers. The degradation of LDLR reduced the absorption of TG‐rich VLDL/LDL particles, 28–31 which agrees with our results relating the low expression of LDLR with the elevated secretion of VLDL. The LDLR mRNA level might affect the protein–water stability as a result of post‐translational modification of LDLR protein 32 .…”

Section: Discussionsupporting

confidence: 91%

Angiopoietin‐like protein 4 promotes very‐low‐density lipoprotein assembly and secretion in bovine hepatocytes in vitro

et al. 2020

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In dairy cows, fatty liver is one of the most common metabolic diseases that occurs during the periparturient period. Angiopoietin‐like protein 4 (ANGPTL4) is a well‐known downstream target of peroxisome proliferator‐activated receptors (PPARs), which regulate the glucose and fatty acid metabolisms. The inhibition of lipoprotein lipase (LPL) activity interferes with the storage of triglycerides (TG) in adipocytes, which plays an essential role in lipid metabolism in rodents. However, it remains unclear whether ANGPTL4 is involved in the pathological process of fatty liver in dairy cows as a result of the regulation of the hepatocellular lipid transport system. This study intended to investigate the effect of ANGPTL4 on the very‐low‐density lipoprotein (VLDL) assembly and secretion in bovine hepatocytes. Bovine hepatocytes were isolated using a modified two‐step perfusion and collagenase digestion process, and treated with different concentrations of ANGPTL4 (0, 4, 12, and 24 ng/ml) for 24 hr. The results showed that a high concentration of ANGPTL4 could significantly increase the extracellular concentration of VLDL while reducing the intracellular content of TG. Thus, it was confirmed that ANGPTL4 could promote the transport of TG in the form of VLDL by partially regulating the expression of related proteins in hepatocytes, thereby contributing to the partial adaptive regulation of lipid transport in dairy cows.

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Section: Discussionsupporting

confidence: 91%

Angiopoietin‐like protein 4 promotes very‐low‐density lipoprotein assembly and secretion in bovine hepatocytes in vitro

et al. 2020

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“…In addition, LDLR is subject to targeted proteolytic cleavage. For example, LDLR was reported recently to undergo γ-secretase-mediated cleavage which in turn induces LDLR lysosomal degradation 10 and the action of an unidentified protease cleaving LDLR within its LA repeats produced a 120 kDa C-terminal fragment (CTF) 11,12 . Further understanding of these proteolytic mechanisms and the role they play could provide additional therapeutic targets for the treatment of hypercholesterolaemia.…”

Section: Introductionmentioning

confidence: 99%

Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake

Banerjee

Andrew

Duff

et al. 2019

Sci Rep

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The development of cardiovascular disease is intimately linked to elevated levels of low-density lipoprotein (LDL) cholesterol in the blood. Hepatic LDL receptor (LDLR) levels regulate the amount of plasma LDL. We identified the secreted zinc metalloproteinase, bone morphogenetic protein 1 (BMP1), as responsible for the cleavage of human LDLR within its extracellular ligand-binding repeats at Gly 171 ↓Asp 172 . The resulting 120 kDa membrane-bound C-terminal fragment (CTF) of LDLR had reduced capacity to bind LDL and when expressed in LDLR null cells had compromised LDL uptake as compared to the full length receptor. Pharmacological inhibition of BMP1 or siRNA-mediated knockdown prevented the generation of the 120 kDa CTF and resulted in an increase in LDL uptake into cells. The 120 kDa CTF was detected in the livers from humans and mice expressing human LDLR. Collectively, these results identify that BMP1 regulates cellular LDL uptake and may provide a target to modulate plasma LDL cholesterol.

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“…Next, to ensure reproducibility of these results, we ablated hepatocyte Nicastrin (25), the γ-secretase targeting subunit necessary for ligand-dependent Notch activation ( L-Ncst mice) (26). Similar to L-DNMAM mice, NASH diet–fed L-Ncst mice showed normal body weight and adiposity (fig.…”

Section: Resultsmentioning

confidence: 99%

Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis

et al. 2018

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Fibrosis is the major determinant of morbidity and mortality in patients with nonalcoholic steatohepatitis (NASH) but has no approved pharmacotherapy in part because of incomplete understanding of its pathogenic mechanisms. Here, we report that hepatocyte Notch activity tracks with disease severity and treatment response in patients with NASH and is similarly increased in a mouse model of diet-induced NASH and liver fibrosis. Hepatocyte-specific Notch loss-of-function mouse models showed attenuated NASH-associated liver fibrosis, demonstrating causality to obesity-induced liver pathology. Conversely, forced activation of hepatocyte Notch induced fibrosis in both chow- and NASH diet–fed mice by increasing Sox9-dependent Osteopontin (Opn) expression and secretion from hepatocytes, which activate resident hepatic stellate cells. In a cross-sectional study, we found that OPN explains the positive correlation between liver Notch activity and fibrosis stage in patients. Further, we developed a Notch inhibitor [Nicastrin antisense oligonucleotide (Ncst ASO)] that reduced fibrosis in NASH diet–fed mice. In summary, these studies demonstrate the pathological role and therapeutic accessibility of the maladaptive hepatocyte Notch response in NASH-associated liver fibrosis.

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γ-Secretase Inhibition Lowers Plasma Triglyceride-Rich Lipoproteins by Stabilizing the LDL Receptor

Cited by 19 publications

References 80 publications

Angiopoietin‐like protein 4 promotes very‐low‐density lipoprotein assembly and secretion in bovine hepatocytes in vitro

Angiopoietin‐like protein 4 promotes very‐low‐density lipoprotein assembly and secretion in bovine hepatocytes in vitro

Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake

Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis

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