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Inclusion of the PPARalpha (peroxisome-proliferator-activated receptor alpha) activator WY 14,643 in the diet of normal mice stimulated the hepatic expression of not only genes of the fatty acid oxidation pathway, but also those of the de novo lipid synthetic pathways. Induction of fatty acid synthase mRNA by WY 14,643 was greater during the light phase of the diurnal cycle, when food intake was low and PPARalpha expression was high. Hepatic fatty acid pathway flux in vivo showed a similar pattern of increases. The abundance of mRNAs for genes involved in hepatic cholesterol synthesis was also increased by WY 14,643, but was associated with a decrease in cholesterogenic carbon flux. None of these changes were apparent in PPARalpha-null mice. Mice of both genotypes showed the expected decreases in 3-hydroxy-3-methylglutaryl-CoA reductase mRNA levels and cholesterol synthesis in response to an increase in dietary cholesterol. The increase in fatty acid synthesis due to WY 14,643 was not mediated by increased expression of SREBP-1c (sterol regulatory element binding protein-1c) mRNA, but by an increase in cleavage of the protein to the active form. An accompanying rise in stearoyl-CoA desaturase mRNA expression suggested that the increase in lipogenesis could have resulted from an alteration in membrane fatty acid composition that influenced SREBP activation.

Objective-Analysis of long-term (30 years) clinical history and response to treatment of 13 patients with the D374Y mutation of PCSK9 (PCSK9 patients) from 4 unrelated white British families compared with 36 white British patients with heterozygous familial hypercholesterolemia attributable to 3 specific mutations in the low-density lipoprotein (LDL) receptor gene (LDLR) known to cause severe phenotype. Methods and Results-The PCSK9 patients, when compared with the LDLR patients, were younger at presentation (20.8Ϯ14.7 versus 30.2Ϯ15.7 years; Pϭ0.003), had higher pretreatment serum cholesterol levels (13.6Ϯ2.9 versus 9.6Ϯ1.6 mmol/L; Pϭ0.004) that remained higher during treatment with simvastatin (10.1Ϯ3.0 versus 6.5Ϯ0.9 mmol/L; Pϭ0.006), atorvastatin (9.6Ϯ2.9 versus 6.4Ϯ1.0 mmol/L; Pϭ0.006), or current lipid-lowering therapy, including LDL apheresis and partial ileal bypass in 2 PCSK9 patients (7.0Ϯ1.6 versus 5.4Ϯ1.0 mmol/L; Pϭ0.001), and were affected Ͼ10 years earlier by premature coronary artery disease (35.2Ϯ4.8 versus 46.8Ϯ8.9 years; Pϭ0.002). LDL from PCSK9 patients competed significantly less well for binding to fibroblast LDL receptors than LDL from either controls or LDLR patients. Conclusions-These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications. Key Words: coronary disease Ⅲ atherosclerosis Ⅲ familial hypercholesterolemia Ⅲ statins Ⅲ ezetimibe F amilial hypercholesterolemia (FH) is a common autosomal dominant disorder caused by mutations in the lowdensity lipoprotein (LDL) receptor gene (LDLR) leading to defective catabolism of plasma LDL by the liver and characterized by elevated levels of LDL cholesterol, tendon xanthomas, and excessive deposition of cholesterol in the arterial wall, causing premature atherosclerosis. 1 An almost identical clinical syndrome to FH, called familial defective apolipoprotein B (apoB), can occur as a result of a dominantly inherited mutation of the ApoB gene, which encodes the ligand for the LDL receptor, causing impaired catabolism of LDL. 2 Recently, heterozygous missense variants in a gene named PCSK9 (protein convertase subtilisin/kexin9) have been described to cosegregate with hypercholesterolemia in families of European origin. [3][4][5][6] PCSK9 encodes a putative protease, which is a member of the subtilisin-like protein convertase family. 7,8 Its physiological role has not yet been elucidated, but there is substantial evidence that it is involved in cholesterol homeostasis. 9 -12 PCSK9 is responsive to sterols and is a putative sterol regulatory element-binding protein (SREBP) target in mice. 11,12 Adenovirus-mediated overexpression of wild-type PCSK9 in mice led to severe hypercholesterolemia by decreasing the amount of LDL receptor protein in the liver without reducing LDL receptor mRNA levels. 13 However, similar overexpression of 2 naturally occurring PCSK9 mis...