👤 T Shimano

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

Dietary medium-chain fatty acids (MCFAs), characterized by chain lengths of 8-12 carbon atoms, have been proposed to have beneficial effects on glucose and lipid metabolism, yet the underlying mechanisms remain elusive. We hypothesized that MCFA intake benefits metabolic health by inducing the release of hormone-like factors. The effects of chow diet, high-fat diet rich in long-chain fatty acids (LCFA HFD) fed ad libitum or pair-fed to a high-fat diet rich in MCFA (MCFA HFD) on glycemia, hepatic gene expression, circulating fibroblast growth factor 21 (FGF21), and liver fat content in both wildtype and Fgf21 knockout mice were investigated. The impact of a single oral dose of an MCFA-rich oil on circulating FGF21 and hepatic Fgf21 mRNA expression was assessed. In flag-tagged Crebh knockin mice and liver-specific Crebh knockout mice, fed LCFA HFD or MCFA HFD, active hepatic CREBH and hepatic Fgf21 mRNA abundance were determined, respectively. MCFA HFD improves glucose tolerance, enhances glucose clearance into brown adipose tissue, and prevents high-fat diet-induced hepatic steatosis in wildtype mice. These benefits are associated with increased liver expression of CREBH target genes (Apoa4 and Apoc2), including Fgf21. Both acute and chronic intake of dietary MCFAs elevate circulating FGF21. Augmented hepatic Fgf21 mRNA following MCFA HFD intake is accompanied by higher levels of active hepatic CREBH; and MCFA-induced hepatic Fgf21 expression is blocked in mice lacking Crebh. Notably, while feeding male and female Fgf21 wildtype mice MCFA HFD results in reduced liver triacylglycerol (TG) levels, this liver TG-lowering effect is blunted in Fgf21 knockout mice fed MCFA HFD. The reduction in liver TG levels observed with MCFA HFD was independent of weight loss. Dietary MCFAs reduce liver fat accumulation via activation of a CREBH-FGF21 signaling axis. Show less

Cyclic adenosine monophosphate-responsive element-binding protein H (CREBH) activates lipoprotein lipase (LPL) activity by modulating apolipoproteins. Activated LPL hydrolyzes triglyceride-rich lipoproteins, such as very low-density lipoprotein (VLDL) and chylomicrons, resulting in remnant lipoproteins. CREBH increases apolipoprotein E (ApoE), a ligand that mediates the clearance of remnant particles and reduces ApoC3, which interferes with remnant clearance. CREBH also improves VLDL receptor (VLDLR) and LDL receptor-related protein 1 (LRP1) protein that mediates remnant clearance. Therefore, CREBH promotes the clearance of remnant particles from the blood, decreasing the atherogenic plaque area. CREBH induces the secretion of fibroblast growth factor 21 (FGF21) into the blood, decreasing plasma triglyceride. CREBH produces ApoA1 and so increases plasma HDL-cholesterol levels. 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

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

The Wnt signaling pathway is essential for development and organogenesis. Wnt signaling stabilizes beta-catenin, which accumulates in the cytoplasm, binds to 1-cell factor (TCF; also known as lymphocyte enhancer-binding factor, LEF) and then upregulates downstream genes. Mutations in CTNNB1 (encoding beta-catenin) or APC (adenomatous polyposis coli) have been reported in human neoplasms including colon cancers and hepatocellular carcinomas (HCCs). Because HCC5 tend to show accumulation of beta-catenin more often than mutations in CTNNB1, we looked for mutations in AXIN1, encoding a key factor for Wnt signaling, in 6 HCC cell lines and 100 primary HCC5. Among the 4 cell lines and 87 HCC5 in which we did not detect CTNNB1 mutations, we identified AXIN1 mutations in 3 cell lines and 6 mutations in 5 of the primary HCCs. In cell lines containing mutations in either gene, we observed increased DNA binding of TCF associated with beta-catenin in nuclei. Adenovirus mediated gene transfer of wild-type AXINI induced apoptosis in hepatocellular and colorectal cancer cells that had accumulated beta-catenin as a consequence of either APC, CTNNB1 or AXIN1 mutation, suggesting that axin may be an effective therapeutic molecule for suppressing growth of hepatocellular and colorectal cancers. Show less