NPC1L1 inhibitor ezetimibe is a reliable therapeutic agent for non-obese patients with nonalcoholic fatty liver disease

Enjoji, Munechika; Machida, Kazuyuki; Kohjima, Motoyuki; Kato, Masaki; Kotoh, Kazuhiro; Matsunaga, Kazuhisa; Nakashima, Mitsuyoshi; Nakamuta, Makoto

doi:10.1186/1476-511x-9-29

Cited by 63 publications

(45 citation statements)

References 20 publications

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“…terol absorption, has been shown to improve the clinical parameters of NAFLD (13). However, the culturing of HepG2 cells with cholesterol did not enhance DPP4 expression, suggesting that cholesterol does not affect the transcriptional regulation of DPP4 in the liver.…”

Section: Discussionmentioning

confidence: 93%

“…We next examined the effect of water-soluble cholesterol, as cholesterol is involved in the pathogenesis of NAFLD (13,14). In addition, its oxidized derivative, oxysterol, is an agonist of liver X receptor (LXR), which transactivates lipogenic transcriptional factors, including sterol regulatory element-binding protein (SREBP)-1c and carbohydrate response element-binding protein (ChREBP) (15).…”

Section: Effects Of Nutritional Factors On the Expression Of Dpp4 Inmentioning

confidence: 99%

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Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism

et al. 2011

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Abstract. Dipeptidyl peptidase-4 (DPP4) is a serine protease that degrades glucagon-like peptide-1 (GLP-1), an incretin hormone that stimulates insulin secretion from pancreatic β-cells. DPP4 is also involved in the regulation of T cellmediated inflammatory processes. These properties of DPP4 suggest that it may play a role in the progression of nonalcoholic fatty liver disease (NAFLD). Hepatic DPP4 mRNA expression levels were analyzed by real-time PCR using liver biopsy samples from 17 NAFLD patients and 10 healthy subjects. In NAFLD patients, we also examined correlations between DPP4 expression levels and metabolic factors, including homeostasis model assessment-insulin resistance (HOMA-IR), body mass index (BMI), and serum cholesterol and triglyceride levels. To examine the potential effects of nutritional factors, DPP4 expression levels were analyzed in HepG2 cells subjected to various culture conditions. Hepatic DPP4 mRNA expression was significantly greater in NAFLD patients than in control subjects. DPP4 expression levels were negatively correlated with HOMA-IR and positively correlated with serum cholesterol levels. In HepG2 cells, high glucose significantly enhanced DPP4 expression, whereas insulin, fatty acids and cholesterol did not. Increased hepatic expression of DPP4 in NAFLD may be associated with metabolic factors, including insulin resistance, and may adversely affect glucose metabolism in this liver disease. IntroductionNon-alcoholic fatty liver disease (NAFLD) is a clinicopathological disorder characterized by the accumulation of triglycerides in hepatocytes. The incidence of NAFLD has increased markedly in recent years, accompanying the increased prevalence of obesity and type 2 diabetes mellitus (T2DM) (1). More than 10% of patients with NAFLD progress to non-alcoholic steatohepatitis (NASH), which is characterized by inflammatory cell infiltration and ballooning of hepatocytes in the liver. Liver cirrhosis and hepatocellular carcinoma occur in several patients with NASH (2). Obesity and insulin resistance (IR) are believed to be involved in the pathogenesis of NAFLD (3). Increased hepatic uptake of fatty acids as a result of elevated triglyceride degradation in adipose tissue causes hepatic fat accumulation. Reactive oxygen species (ROS) produced during lipid oxidation may induce hepatocyte death and inflammatory reactions. IR also reduces glucose uptake in muscles and diminishes insulin-dependent suppression of gluconeogenesis, ultimately progressing to T2DM (4).Dipeptidyl peptidase-4 (DPP4) inhibitors were recently introduced for the treatment of T2DM (5). DPP4 degrades glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion from pancreatic β-cells. DPP4 inhibitors enhance glucose-dependent insulin secretion by suppressing GLP-1 degradation. However, the physiological functions of DPP4 are not fully understood. In addition to its effect on GLP-1, multiple activities of DPP4 have been reported in various cellular processes. Of note, DPP4 seems to influence inflammation by regu...

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Section: Discussionmentioning

confidence: 93%

Section: Effects Of Nutritional Factors On the Expression Of Dpp4 Inmentioning

confidence: 99%

Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism

et al. 2011

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“…The basal values of TG, RLP-C, FPG, IRI and HOMA-IR as well as the changes in HDL-C, RLP-C, IRI, HOMA-IR, LDL-Rm and hs-CRP after ezetimibe treatment were different between the monotherapy and combined therapy groups ( Table 2). Although the percentage of modified-LDL, and profiles of lipoprotein particle size and fatty acid components, but also histological findings of hepatic triglyceride content, steatosis grade, necroinflammatory grade, ballooning score, and NAFLD activity score in patients with obesity and/or NAFLD 7, [22][23][24][25] . Ezetimibe treatment or knockdown of NPC1L1 in hepatocytes reduced hepatic insulin resistance through a reduction in reactive oxygen species and endoplasmic reticulum stress, activation of insulin-induced Akt, and inhibition of SREBP-1 expression in the liver 12,14) .…”

Section: Discussionmentioning

confidence: 99%

“…Ezetimibe was reported to improve the serum ALT level, hepatic steatosis and insulin resistance in both rodents and humans 3,7,[22][23][24][25][26][27] . In the present study, we confirmed that ezetimibe improves insulin resistance by reducing fasting IRI and HOMA-IR.…”

Section: Discussionmentioning

confidence: 99%

Ezetimibe Ameliorates Atherosclerotic and Inflammatory Markers, Atherogenic Lipid Profiles, Insulin Sensitivity, and Liver Dysfunction in Japanese Patients with Hypercholesterolemia

Tamaki

Ueno

Morinaga

et al. 2012

JAT

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Aim: Ezetimibe reduces serum low-density lipoprotein cholesterol (LDL-C) levels by inhibiting intestinal cholesterol absorption; however, the effects of ezetimibe, including its pleiotropic effects, have not been fully clarified. The aims of our study were to examine the efficacy of ezetimibe for hypercholesterolemia and its pleiotropic effects. Methods: Outpatients with hyper LDL-C levels were treated with 10 mg ezetimibe once a day for 12 weeks. Serum lipid profiles, atherosclerotic and inflammatory markers, glucose, insulin, liver function, and cholesterol absorption and synthesis markers were measured before and after treatment. Results: Seventy-five patients treated with ezetimibe monotherapy and 16 patients treated with combined therapy of ezetimibe with different statins completed this study. Following 12 weeks of ezetimibe monotherapy, serum LDL-C, triglyceride, remnant-like particles cholesterol, matrix metalloproteinase-9, insulin, homeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein, the relative mobility of the peak of the LDL fraction, and cholesterol absorption markers were significantly decreased, and high-density lipoprotein cholesterol and lathosterol were significantly increased. In the combined therapy group, LDL-C and cholesterol absorption markers were significantly decreased after treatment. In patients with a high basal ALT level that were treated with monotherapy, ALT and the AST/ALT ratio were significantly decreased and increased, respectively, after treatment. Conclusion: Ezetimibe ameliorated not only atherogenic lipid profiles but also atherosclerotic and inflammatory markers, insulin sensitivity, and liver dysfunction in Japanese hypercholesterolemia patients, suggesting that ezetimibe treatment is a beneficial and effective strategy for the treatment of hypercholesterolemia, especially patients with obesity, metabolic syndrome, and/or fatty liver.

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“…Ezetimibe was released onto the market in the USA in 2002. Three Japanese groups reported pilot studies for estimating the effect of ezetimibe and they showed the clinical efficacy of ezetimibe against NAFLD/NASH by evaluating serum biochemical indices and hepatic histology [93][94][95].…”

Section: Metformin Cq: Are Biguanides Effective For Patients With Nafmentioning

confidence: 99%

Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

et al. 2015

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Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various noninvasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise; however, pharmacological approaches are often necessary.Currently, vitamin E and thiazolidinedione derivatives are the most evidence-based therapeutic options, although the clinical evidence for long-term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 to January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan.

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NPC1L1 inhibitor ezetimibe is a reliable therapeutic agent for non-obese patients with nonalcoholic fatty liver disease

Cited by 63 publications

References 20 publications

Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism

Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism

Ezetimibe Ameliorates Atherosclerotic and Inflammatory Markers, Atherogenic Lipid Profiles, Insulin Sensitivity, and Liver Dysfunction in Japanese Patients with Hypercholesterolemia

Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

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