Genetic determinants of HDL cholesterol (HDL-C) levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G(+l)-to-A mutation(Intl4 A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C 100 mg/dl (n = 130) were screened by PCR single strand conformational polymorphism analysis of the CETP gene. Two other mutations were identified by DNA sequencing or primer-mediated restriction map modification of PCR products: a novel intron 14 splice donor site mutation caused by a T insertion at position +3 from the exonl4/intronl4 boundary (Intl4 T) and a missense mutation (Asp'2 to Gly) within exon 15 (D442G).The Intl4 T mutation was only found in one family. However, the D442G and Intl4 A mutations were highly prevalent in subjects with HDL-C . 60 mg/dl, with combined allele frequencies of 9%, 12%, 21%, and 43% for HDL-C 60-79, 80-99, 100-119, and . 120 mg/dl, respectively. Furthermore, prevalences of the D442G and Intl4 A mutations were extremely high in a general sample of Japanese men (n = 236), with heterozygote frequencies of 7% and 2%, respectively. These two mutations accounted for about 10% of the total variance of HDL-C in this population. The phenotype in a genetic compound heterozygote (Intl4 T and Intl4 A) was similar to that of Intl4 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Intl4 T produces a null allele. In four D442G homozygotes, mean HDL-C levels (86±26 mg/dl) were lower than in Intl4 A homozygotes (158±35 mgldl), reflecting residual CETP activity in plasma. In 47 D442G heterozygotes, mean HDL-C levels were 91±23 mg/dl, similar to the level in D442G homozygotes, and significantly greater than mean HDL-C levels in Intl4 A heterozygotes (69±15 mg/dl). Thus, the D442G mutation acts differently to the null mutations A portion of this paper was presented at the Asian-Pacific Congress on coronary heart disease risk factor held in Hong Kong, January 1994.

LES with BCAA supplementation significantly and rapidly improves liver functioning and CPS in LC patients who have undergone RFA for HCC. Control of blood sugar levels is necessary when calorie-containing BCAA is administrated to LC patients with impaired glucose tolerance.

We investigated the effects of subclasses of plasma LpA-I (HDL containing apoA-I but not apoA-II) on cholesterol esterification in plasma and net cholesterol efflux from foam cells. LpA-I was composed of particles of three diameters: large (11.1 nm; Lg-LpA-I), medium (8.8 nm; Md-LpA-I), and small (7.7 nm; Sm-LpA-I). Plasma concentrations of LpA-I were positively correlated only with the level of Lg-LpA-I. Plasma concentrations of Lg-LpA-I were inversely correlated with the rate of cholesterol esterification in plasma and VLDL- and LDL-depleted plasma. Plasma concentrations of Md-LpA-I and Sm-LpA-I did not correlate with the rate of cholesterol esterification in plasma or VLDL- and LDL-depleted plasma. When macrophage foam cells were incubated with Md- and Sm-LpA-I, cellular cholesterol mass was reduced by approximately 70%. In contrast, the cellular cholesterol-reducing capacity of Lg-LpA-I was negligible. Lg-LpA-I inhibited net cholesterol removal from foam cells that was mediated by Md- and Sm-LpA-I and cholesteryl ester production with these particles. These results suggest that Md- and Sm-LpA-I may actively participate in cellular cholesterol removal and cholesterol esterification in plasma and HDL, while Lg-LpA-I may regulate these functions of Md- and Sm-LpA-I.

We report a 39-year-old Japanese man with HDL and apoA-I deficiency as well as data from members of his family. Corneal opacity and a stomatocyte were found but not tonsillar hypertrophy, xanthomas, or splenomegaly. His serum HDL cholesterol, apoA-I, apoA-II, and LDL cholesterol levels were t mg/dL, < 3 mg/dL, 6 mg/dL, and 175 mg/dL, respectively. Plasma triglyceride, phospholipid, apoB, apoC-III, and apoE levels were all within normal limits. Lecithin:cholesterol acyltransferase activity was half of normal, while lipoprotein lipase and hepatic triglyceride lipase activities were within normal limits. ApoA-I deficiency was confirmed by combined isoelectric focusing and sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by an immunoblotting method. We surveyed the apoA-I gene of the patient and five of his family members by direct sequencing after amplification by polymerase chain reaction and found a codon 8 nonsense mutation (TGG --> TAG, Trp --> stop) in exon 3 of the apoA-I gene. The results of a pedigree analysis by DNA sequencing and restricted fragment length polymorphism (Sty I) were consistent with an autosomal codominant trait. Coronary angiography was performed to evaluate coronary atherosclerosis, but no significant luminal narrowing was detected. An intracoronary ultrasound study showed mild intimal hyperplasia in segment 6. In summary, this is a case of apoA-I deficiency without evidence of coronary heart disease.

Background and aimsInsulin resistance and cytokine production are key mechanisms leading to fatty change in the liver and may produce nonalcoholic steatohepatitis (NASH). Oxidative stress may also contribute to clinical progression from simple fatty liver (FL) to NASH. A therapy for insulin resistance and antioxidant has been applied to treat NASH, yet these treatments are not fully established. In the present study, we have evaluated whether an antioxidant agent, glutathione, prevents the development of NASH from FL.Materials and methodsFive patients with FL and 10 with NASH were enrolled in the study. Three hundred milligrams per day of glutathione was given orally to patients with nonalcoholic fatty liver disease (NAFLD) every day, and an oxidative stress marker and biochemical tests were analyzed before treatment and 1 and 3 months after starting the treatment. We measured serum levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and gamma-glutamyltranspeptidase (GGT). Immunohistochemistry for glutathione was performed on formalin fixed liver specimens obtained from liver biopsies.ResultsBefore treatment, the NASH group had higher serum 8-OHdG and lower serum glutathione levels than the FL group. Immunohistochemistry revealed that a strong expression of glutathione was observed in zone 3 in both NASH and FL before treatment. Serum levels of alanine transaminase and 8-OHdG were significantly decreased after treatment in the NASH group. Gamma-glutamyltranspeptidase was decreased after treatment, although the decrease was statistically not significant.DiscussionThe present pilot study demonstrated that antioxidant therapy with glutathione may reduce the pathological oxidative stress in the liver in NASH, preventing the progression from NAFLD to NASH.How to cite this articleIrie M, Sohda T, Anan A, Fukunaga A, Takata K, Tanaka T, Yokoyama K, Morihara D, Takeyama Y, Shakado S, Sakisaka S. Reduced Glutathione suppresses Oxidative Stress in Nonalcoholic Fatty Liver Disease. Euroasian J Hepato-Gastroenterol 2016;6(1):13-18.

Sinus bradycardia is a well-known consequence of stimulation of presynaptic α2 adrenergic receptors due the adminstration of dexmedetomidine. One of the most serious adverse effects of dexmedetomidine is cardiac arrest. Some cases demonstrating such an arrest due to the indiscriminate use of this drug were recently reported. We continuously administered dexmedetomidine to a 56-year-old male patient at a rate of 0.3 μg/kg/h (lower than the recommended dose) without initial dosing for sedation in an intensive care unit. The patient had undergone open cardiac surgery and atrial pacing was maintained at a fixed rate, 90/min. The PQ interval in electrocardiography gradually prolonged during the infusion; finally, complete atrioventricular block and subsequent cardiac arrest occurred. Immediate cardiopulmonary resuscitation was carried out, including re-intubation, and recovery of spontaneous circulation was attained 15 min after the event. The patient was discharged from hospital on the 25th postoperative day without any neurological complications.

Fractional esterification rate of cholesterol in high density lipoprotein (HDL) (FER[HDL]) can predict the size distribution and physicochemical characteristics of HDL in plasma. In the present study, we investigated the correlation of FER(HDL) with the particle size of low density lipoprotein (LDL) (LDL-size) in 111 patients (81 males and 30 females) with coronary heart disease (CHD). The correlations of FER(HDL) and LDL-size with conventional lipid and lipoprotein parameters were also studied. FER(HDL) was closely associated with LDL-size (males: r = -0.618, females: r = -0.629, P < 0.001). Plasma levels of TG, HDL-cholesterol (HDL-C), HDL2-cholesterol (HDL2-C) and apo B were also associated with LDL-size in male CHD patients (r = -0.534, 0.314, 0.358, and -0.482, P < 0.01 or 0.001), while plasma levels of TG and apo B were associated with LDL-size in female patients (r = -0.350 and -0.348, P < 0.05). In a stepwise multiple regression analysis, FER(HDL) alone accounted for 38 and 40% of the variability in LDL-size in male and female CHD patients, respectively. Other parameters accounted for an additional 6-10%. With respect to the relation between FER(HDL) and HDL subfractions, FER(HDL) related only to HDL2-C (males: r = -0.640, females: r = -0.652, P < 0.001). This result suggests that FER(HDL) is better able to predict the presence (or absence) of large HDL, rather than that of small HDL. All these data taken together, suggest that FER(HDL) is a useful tool to predict the particle size of both LDL and HDL, even in CHD patients.

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