👤 Yoshinori Osaki

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of early onset atherosclerosis. Evinacumab, an angiopoietin-like protein 3 (ANGPTL3)-inhibiting monoclonal antibody, lowers LDL-C independently of LDL receptor activity. However, its effects on other lipid-related markers remain poorly investigated in real-world clinical practice. We herein report a 54-year-old Japanese woman with genetically confirmed compound heterozygous familial hypercholesterolemia (FH) treated with evinacumab in combination with other lipid-lowering agents. Lipoprotein apheresis was continued every two weeks throughout the treatment. Serum sampling before and after evinacumab administration found that, following evinacumab initiation, LDL-C decreased from 324 to 205 mg/dL (reduction of 119 mg/dL, -36.7%) and triglycerides from 155 to 51 mg/dL (reduction of 103 mg/dL, -66.8%). Notably, atherosclerosis-related markers showed substantial reductions, with remnant-like particle cholesterol (RLP-C) decreasing from 10.5 to ＜2.0 mg/dL, small dense LDL-C (sdLDL-C) from 80.2 to 22.1 mg/dL, and malondialdehyde-modified LDL (MDA-LDL) from 105 to 87 mg/dL. Apolipoproteins (ApoB, ApoC2, ApoC3, ApoE, and ApoA5) decreased as well. No significant changes were observed in lipoprotein (a), free fatty acids, interleukin-6, or high-sensitivity C-reactive protein levels. This is the first clinical report to comprehensively evaluate the lipid-modifying effects of evinacumab in a Japanese HoFH patient. In this case, evinacumab was highly efficacious against atherosclerosis-related markers and apolipoproteins, beyond simple LDL-C reduction, suggesting additional cardiovascular benefits. These findings provide mechanistic insights that may inform therapeutic strategies for the management of HoFH. Show less

cAMP responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor involved in the maintenance of lipid metabolism in the liver and small intestine. CREB3L3 controls hepatic triglyceride and glucose metabolism by activating plasma fibroblast growth factor 21 (FGF21) and lipoprotein lipase. In this study, we intended to clarify its effect on atherosclerosis. CREB3L3-deficifient, liver-specific CREB3L3 knockout, intestine-specific CREB3L3 knockout, both liver- and intestine-specific CREB3L3 knockout, and liver CREB3L3 transgenic mice were crossed with LDLR CREB3L3 ablation in LDLR CREB3L3 has multi-potent protective effects against atherosclerosis owing to new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions. Show less

Eukaryotic cells assemble actomyosin rings during cytokinesis to function as force-generating machines to drive membrane invagination and to counteract the intracellular pressure and the cell surface tension. How the extracellular matrix affects actomyosin ring contraction has not been fully explored. While studying the Show less

The transcription factor cyclic AMP-responsive element-binding protein H (CREBH, encoded by To investigate the influence of intestinal CREBH on cholesterol metabolism, we compared plasma, bile, fecal, and tissue cholesterol levels between wild-type (WT) mice and mice overexpressing active human CREBH mainly in the small intestine (CREBH Tg mice) under different dietary conditions. Plasma cholesterol, hepatic lipid, and cholesterol crystal formation in the gallbladder were lower in CREBH Tg mice fed a lithogenic diet (LD) than in LD-fed WTs, while fecal cholesterol output was higher in the former. These results suggest that intestinal CREBH overexpression suppresses cholesterol absorption, leading to reduced plasma cholesterol, limited hepatic supply, and greater excretion. The expression of Niemann-Pick C1-like 1 ( Intestinal CREBH regulates dietary cholesterol flow from the small intestine by controlling the expression of multiple intestinal transporters. We propose that intestinal CREBH could be a therapeutic target for hypercholesterolemia. Show less

Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted in response to dietary fat and glucose. The blood GIP level is elevated in obesity and diabetes. GIP stimulates proinflammatory gene expression and impairs insulin sensitivity in cultured adipocytes. In obesity, hypoxia within adipose tissue can induce inflammation. The aims of this study were 1) to examine the proinflammatory effect of increased GIP signaling in adipose tissues in vivo and 2) to clarify the association between GIP and hypoxic signaling in adipose tissue inflammation. We administered GIP intraperitoneally to misty (lean) and db/db (obese) mice and examined adipose tissue inflammation and insulin sensitivity. We also examined the effects of GIP and hypoxia on expression of the GIP receptor (GIPR) gene and proinflammatory genes in 3T3-L1 adipocytes. GIP administration increased monocyte chemoattractant protein-1 (MCP-1) expression and macrophage infiltration into adipose tissue and increased blood glucose in db/db mice. GIPR and hypoxia-inducible factor-1α (HIF-1α) expressions were positively correlated in the adipose tissue in mice. GIPR expression increased dramatically in differentiated adipocytes. GIP treatment of adipocytes increased MCP-1 and interleukin-6 (IL-6) production. Adipocytes cultured either with RAW 264 macrophages or under hypoxia expressed more GIPR and HIF-1α, and GIP treatment increased gene expression of plasminogen activator inhibitor 1 and IL-6. HIF-1α gene silencing diminished both macrophage- and hypoxia-induced GIPR expression and GIP-induced IL-6 expression in adipocytes. Thus, increased GIP signaling plays a significant role in adipose tissue inflammation and thereby insulin resistance in obese mice, and HIF-1α may contribute to this process. Show less