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Although patients with nonalcoholic fatty liver disease have been reported to have cardiac dysfunction, and appropriate model has not been reported. We established a novel mouse model of diet-induced steatohepatitis-related cardiomyopathy and evaluated the effect of pemafibrate. C57Bl/6 male mice were fed a (1) chow diet (C), (2) high-fat, high-cholesterol, high-sucrose, bile acid diet (NASH diet; N), or (3) N with pemafibrate 0.1 mg/kg (NP) for 8 weeks. In the liver, macrophage infiltration and fibrosis in the liver was observed in the N group compared to the C group, suggesting steatohepatitis. Free cholesterol accumulated, and cholesterol crystals were observed. In the heart, free cholesterol similarly accumulated and concentric hypertrophy was observed. Ultrahigh magnetic field magnetic resonance imaging revealed that the left ventricular (LV) ejection fraction (EF) was attenuated and LV strain was focally impaired. RNA sequencing demonstrated that the NOD-like receptor and PI3 kinase-Akt pathways were enhanced. mRNA and protein expression of inflammasome-related genes, such as Caspase-1, NLRP3, and IL-1β, were upregulated in both the liver and heart. In the NP compared to the N group, steatohepatitis, hepatic steatosis, and cardiac dysfunction were suppressed. Sequential administration of pemafibrate after the development of steatohepatitis-related cardiomyopathy recovered hepatic fibrosis and cardiac dysfunction.

Purpose of ReviewReduction of serum low-density lipoprotein cholesterol (LDL-C) levels by statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has been shown to significantly reduce cardiovascular events risk. However, fasting and postprandial hypertriglyceridemia as well as reduced high-density lipoprotein cholesterol (HDL-C) remain as residual risk factors of atherosclerotic cardiovascular diseases (ASCVD). To treat patients with hypertriglyceridemia and/or low HDL-C, drugs such as fibrates, nicotinic acids, and n-3 polyunsaturated fatty acids have been used. However, fibrates were demonstrated to cause side effects such as liver dysfunction and increase in creatinine levels, and thus large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD. The failure could be attributed to their low selectivity and potency for binding to peroxisome proliferator-activated receptor (PPAR) α. To resolve these issues, the concept of selective PPARα modulator (SPPARMα) with a superior balance of efficacy and safety has been proposed and pemafibrate (K-877) has been developed.Recent FindingsPemafibrate, one of SPPARMsα, was synthesized by Kowa Company, Ltd. for better efficiency and safety. Clinical trials in Japan have established the superiority of pemafibrate on effects on serum triglycerides (TG) reduction and HDL-C elevation as well safety. Although available fibrates showed worsening of liver and kidney function test values, pemafibrate indicated improved liver function test values and was less likely to increase serum creatinine or decrease estimated glomerular filtration rate (eGFR). Very few drug-drug interactions were observed even when used concomitantly with statins. Furthermore, pemafibrate is metabolized in the liver and excreted into the bile, while many of available fibrates are mainly excreted from the kidney. Therefore, pemafibrate can be used safely even in patients with impaired renal function since there is no significant increase in its blood concentration. A large-scale trial of pemafibrate, PROMINENT, for dyslipidemic patients with type 2 diabetes is ongoing.SummaryPemafibrate is one of novel SPPARMsα and has superior benefit-risk balance compared to conventional fibrates and can be applicable for patients for whom the usage of existing fibrates is difficult such as those who are taking statins or patients with renal dysfunction. In the current review, all the recent data on pemafibrate will be summarized.

Comprehensive risk management for the prevention of cerebro- cardiovascular diseases in Japan

U-shaped or J-shaped relationships have been demonstrated between BMI and all-cause or cardiovascular mortality. Now, a study has demonstrated the correlation of increased waist circumference, high adipose tissue mass and low adipose tissue-free mass with all-cause and cardiovascular mortality in an Asian population.

Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available, are poorly understood. Despite the fact that its synthetic agonists induce fatty liver, the liver X receptor (LXR) transcription factor remains a target of interest because of its anti-atherogenic, cholesterol removal, and anti-inflammatory activities. Here we show that tetratricopeptide repeat domain protein 39B (Ttc39b, C9orf52) (T39), a high-density lipoprotein gene discovered in human genome-wide association studies, promotes the ubiquitination and degradation of LXR. Chow-fed mice lacking T39 (T39(-/-)) display increased high-density lipoprotein cholesterol levels associated with increased enterocyte ATP-binding cassette transporter A1 (Abca1) expression and increased LXR protein without change in LXR messenger RNA. When challenged with a high fat/high cholesterol/bile salt diet, T39(-/-) mice or mice with hepatocyte-specific T39 deficiency show increased hepatic LXR protein and target gene expression, and unexpectedly protection from steatohepatitis and death. Mice fed a Western-type diet and lacking low-density lipoprotein receptor (Ldlr(-/-)T39(-/-)) show decreased fatty liver, increased high-density lipoprotein, decreased low-density lipoprotein, and reduced atherosclerosis. In addition to increasing hepatic Abcg5/8 expression and limiting dietary cholesterol absorption, T39 deficiency inhibits hepatic sterol regulatory element-binding protein 1 (SREBP-1, ADD1) processing. This is explained by an increase in microsomal phospholipids containing polyunsaturated fatty acids, linked to an LXRα-dependent increase in expression of enzymes mediating phosphatidylcholine biosynthesis and incorporation of polyunsaturated fatty acids into phospholipids. The preservation of endogenous LXR protein activates a beneficial profile of gene expression that promotes cholesterol removal and inhibits lipogenesis. T39 inhibition could be an effective strategy for reducing both steatohepatitis and atherosclerosis.

After publication of this article[1], we noted formatting errors in Table 2. Elapsed time (h) columns at lines 25 to 43 were out of alignment and the true 8h data were missing. The corrected version of table 2 is below (Table 1).

Hyper-low-density lipoprotein (LDL)-cholesterolaemia is a potent risk factor for coronary atherosclerosis. We have recently demonstrated that a cluster of risk factors including insulin resistance, glucose intolerance, hypertriglyceridaemia, and hypertension based on intra-abdominal visceral fat accumulation are closely related to coronary artery disease. In the current study, we evaluated the relationship between visceral fat accumulation and the severity and distribution of coronary atherosclerosis in familial hypercholesterolaemia (FH).The effect of visceral fat accumulation on coronary lesions and risk factors in patients with FH was investigated.Thirty-one male patients with heterozygous FH who underwent coronary angiography.Abdominal fat distribution was estimated by a cross-sectional computed tomographic scan at the umbilical level. Plasma lipid, glucose and insulin concentrations and blood pressure were measured. A 75 g oral glucose tolerance test was also performed.The patients were divided into two groups according to the degree of visceral fat accumulation. Fifteen patients had high visceral fat accumulation (High VF group) and 16 patients had normal visceral fat accumulation (Normal VF group). Body mass index (BMI) and subcutaneous fat area were significantly higher in the high VF group. Baseline serum triglyceride was significantly higher and baseline low-density lipoprotein (LDL)-cholesterol and reduction of LDL-cholesterol during treatment were significantly lower in High VF group. Fasting plasma glucose and insulin concentrations, and systolic and diastolic pressures were significantly higher in the High VF group. Significant correlations were found between visceral fat area and the sum of the glucose and insulin concentration during an oral glucose tolerance test. Visceral fat area was significantly correlated with the severity of coronary stenosis index. Distal coronary lesions were significantly more frequent in the High VF group. Moreover, the correlation between the visceral fat area and coronary stenosis index was found to be independent of age, BMI, and subcutaneous fat area by multiple regression analysis.Visceral fat accumulation is a potent cardiovascular risk factor in heterozygous FH.

The presence of obesity increases the risk of thrombotic vascular diseases. The role of fat accumulation and its effect on plasminogen activator inhibitor-1 (PAI-1) levels was investigated in humans and animals. Plasma PAI-1 levels were closely correlated with visceral fat area but not with subcutaneous fat area in human subjects. PAI-1 mRNA was detected in both types of fat tissue in obese rats but increased only in visceral fat during the development of obesity. These data suggest that an enhanced expression of the PAI-1 gene in visceral fat may increase plasma levels and may have a role in the development of vascular disease in visceral obesity.