Murray W. Huff

NPC1L1: Evolution From Pharmacological Target to Physiological Sterol Transporter

Niemann-Pick C1-like 1 protein (NPC1L1) was recently shown to be the molecular target of the cholesterol absorption inhibitor class of drugs, of which ezetimibe is the first widely used member. Since its discovery, NPC1L1 has also been shown to play a focal physiological role in intestinal absorption of sterols, including plant sterols and cholesterol. Evidence in support of this new metabolic pathway has been garnered not only through human, animal, and cell studies of function but also through the use of human genetics as an approach to study the association of NPC1L1 sequence variation with metabolic and drug-response phenotypes. The example of NPC1L1 shows how the elucidation of a pharmacological target can serve as a means to gain understanding of a key physiological pathway.

Naringenin prevents cholesterol-induced systemic inflammation, metabolic dysregulation, and atherosclerosis in Ldlr−/− mice

Obesity-associated chronic inflammation contributes to metabolic dysfunction and propagates atherosclerosis. Recent evidence suggests that increased dietary cholesterol exacerbates inflammation in adipose tissue and liver, contributing to the proatherogenic milieu. The ability of the citrus flavonoid naringenin to prevent these cholesterol-induced perturbations is unknown. To assess the ability of naringenin to prevent the amplified inflammatory response and atherosclerosis induced by dietary cholesterol, male Ldlr−/− mice were fed either a cholesterol-enriched high-fat or low-fat diet supplemented with 3% naringenin for 12 weeks. Naringenin, through induction of hepatic fatty acid (FA) oxidation and attenuation of FA synthesis, prevented hepatic steatosis, hepatic VLDL overproduction, and hyperlipidemia induced by both cholesterol-rich diets. Naringenin attenuated hepatic macrophage infiltration and inflammation stimulated by dietary cholesterol. Insulin resistance, adipose tissue expansion, and inflammation were alleviated by naringenin. Naringenin attenuated the cholesterol-induced formation of both foam cells and expression of inflammatory markers in peritoneal macrophages. Naringenin significantly decreased atherosclerosis and inhibited the formation of complex lesions, which was associated with normalized aortic lipids and a reversal of aortic inflammation. We demonstrate that in mice fed cholesterol-enriched diets, naringenin attenuates peripheral and systemic inflammation, leading to protection from atherosclerosis. These studies offer a therapeutically relevant alternative for the prevention of cholesterol-induced metabolic dysregulation.

Elevated Serum C-Reactive Protein and Free Fatty Acids Among Nondiabetic Carriers of Missense Mutations in the Gene Encoding Lamin A/C (LMNA) With Partial Lipodystrophy

Objective—Dunnigan-type familial partial lipodystrophy (FPLD) due to mutant LMNA is a monogenic form of insulin resistance. Affected subjects, especially women, are at increased risk of early coronary heart disease (CHD). Although common insulin resistance is associated with several biochemical perturbations, including elevated C-reactive protein (CRP), the biochemical profile in subjects with mutant LMNA is incompletely defined. Methods and Results—We studied 35 nondiabetic adult FPLD subjects (of whom 24 were women) with either the LMNA R482Q or R482W missense mutations and 51 matched normal first-degree relatives (of whom 27 were women). Compared with normal controls, LMNA mutation carriers had significantly higher plasma insulin and more dyslipidemia, higher mean triglycerides and lower HDL cholesterol, significantly higher nonesterified free fatty acids and CRP, and significantly lower leptin and adiponectin than controls. Subgroup analyses showed that these differences were more pronounced in women. Other biomarkers such as resistin, fibrinogen, and plasminogen activator inhibitor-1 were not different between groups. Conclusions—LMNA mutations in nondiabetic patients with FPLD are associated with several metabolic and biochemical changes, particularly in women. The unfavorable profile might contribute to the increased susceptibility to CHD seen in LMNA mutation carriers.

Effect of amlodipine on hemodynamic and endocrine responses to mental stress

Little is known about the effects of antihypertensive drugs on hemodynamic responses to mental stress. We studied 24 patients with mild-to-moderate hypertension in a double-blind random-sequence crossover study comparing placebo with amlodipine titrated up from 5 to 10 mg daily. After 1 month of treatment, the subjects performed 20 min of a frustrating cognitive task. At baseline before task, amlodipine significantly reduced systolic pressure (128.9+/-8.2 mm Hg v 140.3+/-10.7 mm Hg, P < .001), diastolic pressure (81.7+/-7.7 mm Hg v 90+/-7.5 mm Hg, P < .001), and total peripheral resistance (37.5+/-15 v 45.6+/-23.7 mm Hg/L/min, P < .05), while elevating baseline norepinephrine levels (2286+/-731 pmol/L v 1788+/-546 pmol/L, P < .001). Blood pressure during the stress task was significantly less with amlodipine than with placebo (systolic 142.3+/-12.3 mm Hg v 150.9+/-14.6 mm Hg, P < .001; diastolic 87.9+/-8.4 mm Hg v 97.7+/-9.3 mm Hg, P < .001), whereas norepinephrine was significantly higher (2754+/-1007 pmol/L v 1970+/-740 pmol/L, P < .001). There were no significant differences in cardiac output, plasma lipids or lipoproteins, or markers of platelet activation. Heart rate increased significantly during stress, but there was no significant difference between amlodipine and placebo either at baseline or during stress. Our conclusion is that amlodipine reduces blood pressure at baseline and during mental stress, but raises basal and stress-related plasma catecholamines. This finding may have implications for the recent controversy over the safety of calcium channel antagonists, and suggests the potential relevance of combining amlodipine with adrenergic blockers.