Regular feeding plays an important role in cholesterol homeostasis through the liver circadian clock.

RATIONALE: Peripheral clock control and the relevance of the circadian rhythm to physiology and disease are major questions in mammalian circadian biology. OBJECTIVE: We examined the physiological functions of the liver clock. METHODS AND RESULTS: We established a suppressed feeding schedule regimen constituting a high-cholesterol diet delivered every 6 hours without changes in energy and cholesterol intake. We found that rats exposed to this regimen developed hypercholesteremia. In the liver, the rhythmicity of expression of several clock genes was disrupted. Furthermore, the nocturnal expression of the CYP7A1 gene, which encodes the rate-limiting enzyme for the conversion of cholesterol to bile acids, was shifted to a diurnal pattern. Indeed, suppression of a regular feeding rhythm increased the secretion rate of very-low-density lipoprotein cholesterol from the liver and decreased the excretion of fecal bile acids. CONCLUSIONS: Our results demonstrated that not only the amount and quality of food but also the timing of meals has crucial health implications.

Open-label multicenter registry on the outcomes of peripheral arterial disease treated by balloon angioplasty with optical frequency domain imaging in superficial femoral artery and popliteal artery (OCEAN-SFA study).

Although balloon angioplasty for femoropopliteal artery lesions has been associated with restenosis rates of up to 60% at 12 months, the mechanism of restenosis has not been fully evaluated. The aim of this study was to evaluate the relationship between the vascular features observed on optical frequency domain imaging (OFDI) before and after balloon angioplasty of femoropopliteal artery lesions, and restenosis at 6 months. This study was a prospective multicenter single arm study. OFDI was performed before and after balloon angioplasty and plaque characteristics and vascular features, along with de novo lesions, were assessed. The primary outcome was the presence or absence of restenosis 6 months after balloon angioplasty. Residual platelet reactivity was assessed according to VerifyNow platelet reactivity units (PRUs). The number of patients completing 6 months of follow-up was 47, of which 14 had developed restenosis. Maximum thickness of the dissection flap (odds ratio (OR) 2.71; 95% confidence interval [0.9-8.0]; p = 0.071) and lesion length were identified as risk factors for restenosis (OR 1.015; 95% confidence interval [0.001-0.029]; p = 0.039). The mean PRU at the time of treatment in patients with restenosis was significantly higher than in those without restenosis (286.3 ± 82.6 vs. 208.5 ± 03.6, p = 0.026). Long lesions and major dissection on OFDI after balloon angioplasty for femoropopliteal artery lesions increase restenosis at 6 months. In addition, high residual platelet reactivity at the time of EVT may also be a risk factor for restenosis.Clinical Trial Registration Number UMIN000021120.

Real-time monitoring in three-dimensional hepatocytes reveals that insulin acts as a synchronizer for liver clock.

Resetting the peripheral clock and understanding the integration between the circadian rhythm and metabolic pathways are fundamental questions. To test whether insulin acts as a synchronizer for the hepatic clock by cell-autonomous mechanisms, the phase-resetting capabilities of insulin were investigated in cultured hepatic cells. We provide evidence that three-dimensional (3D) cell culture conditions that preserve the differentiated state of primary hepatocytes sustained the robustness of the molecular clock, while this robustness rapidly dampened under classical monolayer cell culture conditions. Herein, we established a 3D cell culture system coupled with a real-time luciferase reporter, and demonstrated that insulin directly regulates the phase entrainment of hepatocyte circadian oscillators. We found that insulin-deficient diabetic rats had a pronounced phase advance in their hepatic clock. Subsequently, a single administration of insulin induced phase-dependent bi-directional phase shifts in diabetic rat livers. Our results clearly demonstrate that insulin is a liver clock synchronizer.