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Zhang Y.,Qingdao University | Zhang Y.,Qingdao Municipal Hospital | Lu L.,Digestive Disease Key Laboratory of Qingdao | Lu L.,Qingdao Municipal Hospital | And 7 more authors.
Hepatitis Monthly | Year: 2016

Context: An optimal therapeutic strategy has not yet been identified for the pharmacological treatment of intrahepatic cholestasis of pregnancy (ICP). The aim of this study was to evaluate the efficacy and safety of ursodeoxycholic acid (UDCA) and Sadenosylmethionine (SAMe) in the treatment of ICP, both individually and in combination. Evidence Acquisition: Ameta-analysis of all randomized controlled trials (RCTs) comparing UDCA, SAMe, and combination therapy was performed.We carried out a literature search using pubmed, embase, the cochrane register of controlled trials, and the science citation index of web of science. The maternal clinical and biochemical responses, including pruritus scores, total bilirubin, total bile acids, alanine aminotransferase, and aspartate transaminase, were evaluated. Safety assessments, including preterm delivery, cesarean section, and meconium-stained amniotic fluid, were also analyzed. Results: Five RCTs including 311 patients were evaluated. In comparison to SAMe, UDCA significantly reduced the pruritus score (OR =-0.45, 95% confidence interval [CI]:-0.66 to-0.25, P < 0.0001) and improved the levels of total bile acids (TBAs; OR =-0.59, 95% CI:-0.99 to-0.30, P < 0.0001) and alanine aminotransferase (ALT; OR =-0.38, 95% CI:-0.66 to-0.09, P = 0.01). UDCA was associated with significantly lower preterm delivery rates than SAMe (RR = 0.48, 95% CI: 0.32-0.72, P = 0.0004). Interestingly, combination therapy significantly reduced total bilirubin (TB; vs. SAMe, OR =-0.41, 95% CI,-0.74 to-0.08, P = 0.02), aspartate transaminase (AST; vs. UDCA, OR =-0.40, 95% CI,-0.74 to-0.06, P = 0.02), and the rate of preterm delivery (vs. SAMe, OR = 0.62, 95% CI, 0.42-0.91, P = 0.02), in comparison with either drug administered alone. Conclusions: UDCA decreased the pruritus score, TBA, and ALT levels more effectively than SAMe, reducing the rate of preterm delivery for ICP. © 2016, Kowsar Corp.


Li X.-L.,Dalian Medical University | Sui J.-Q.,Qingdao Municipal Hospital | Lu L.-L.,Digestive Disease Key Laboratory of Qingdao | Lu L.-L.,Qingdao Municipal Hospital | And 9 more authors.
Lipids in Health and Disease | Year: 2016

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease which represents a wide spectrum of hepatic damage. Several studies have reported that NAFLD is a strong independent risk factor for coronary artery disease (CAD). And patients with NAFLD are at higher risk and suggested undergoperiodic cardiovascular risk assessment. Cardiovascular disease (CVD) is responsible for the main cause of death in patients with NAFLD, and is mostly influenced by genetic factors. Both NAFLD and CAD are heterogeneous disease. Common pathways involved in the pathogenesis of NAFLD and CAD includes insulin resistance (IR), atherogenic dyslipidemia, subclinical inflammation, oxidative stress, etc. Genomic characteristics of these two diseases have been widely studied, further research about the association of these two diseases draws attention. The gene polymorphisms of adiponectin-encoding gene (ADIPOQ), leptin receptor (LEPR), apolipoprotein C3 (APOC3), peroxisome proliferator-activated receptors (PPAR), sterol regulatory elementbinding proteins (SREBP), transmembrane 6 superfamily member 2 (TM6SF2), microsomal triglyceride transfer protein (MTTP), tumor necrosis factors-alpha (TNF-α) and manganese superoxide dismutase (MnSOD) have been reported to be related to NAFLD and CAD. In this review, we aimed to provide an overview of recent insights into the genetic basis of NAFLD and CAD. © 2016 Li et al.


An B.-Q.,Nanjing Medical University | Lu L.-L.,Digestive Disease Key Laboratory of Qingdao | Lu L.-L.,Qingdao Municipal Hospital | Yuan C.,Nanjing Medical University | And 6 more authors.
Hepatitis Monthly | Year: 2016

Background: Leptin receptor (LEPR) polymorphisms have been reported to be associated with lipid metabolism and insulin resistance in various populations. However, whether LEPR polymorphisms are associated with the risks of non-alcoholic fatty liver disease (NAFLD) and coronary atherosclerosis in the Chinese Han population remains unknown. Objectives: To investigate the association of LEPR polymorphisms at Q223R and K109R with the risks of NAFLD and coronary atherosclerosis in the Chinese Han population. Patients and Methods: Genotypes of LEPRQ223R and K109R were determined by polymerase chain reaction followed by sequencing in patients with NAFLD (n = 554), coronary atherosclerosis (n = 421), and healthy controls (n = 550). Serum lipid profiles were determined using biochemical methods. Pearson’s χ2 test was used to check for Hardy-Weinberg equilibrium and to analyze the distributions of genotypes’ alleles between groups. Baseline characteristics were analyzed using student’s t-test, paired-samples t-test, or the χ2 test where appropriate. Results: The LEPRQ223R A allele significantly reduced the risks of both NAFLD and coronary atherosclerosis (OR = 0.683, 95% CI: 0.527 -0.884, P = 0.004 andOR= 0.724, 95% CI: 0.548 -0.955, P = 0.022, respectively). Compared to controls, no significant differences in the genotype and allele frequencies of K109R were found in the NAFLD and coronary atherosclerosis populations, respectively. However, there was a significantly increased risk of coronary atherosclerosis in NAFLD patients who carried the K109R A allele (OR = 2.283, 95% CI: 1.556 -3.348, P < 0.001). Conclusions: LEPR Q223R polymorphisms may confer a significant risk of NAFLD and coronary atherosclerosis. The A allele in the K109R polymorphism might be considered an independent risk factor for coronary atherosclerosis in NAFLD patients. © 2016, Kowsar Corp.


Liu Y.,Qingdao University | Liu Y.,Qingdao Municipal Hospital | Lu L.-L.,Digestive Disease Key Laboratory of Qingdao | Lu L.-L.,Qingdao Municipal Hospital | And 8 more authors.
Lipids in Health and Disease | Year: 2016

Background: Cardiovascular disease (CAD) responsible and nonalcoholic fatty liver disease (NAFLD) are both metabolic diseases, and they are mostly influenced by genetic factors. The aim of our study is to evaluate the relationship between angiotensin II type-1 receptor (AGTR1) gene rs3772622 polymorphisms and the risk of developing coronary artery disease (CAD) in Chinese patients with NAFLD. Methods: Genotype for AGTR1 rs3772622 in 574 NAFLD patients with CAD or 589 NAFLD patients without CAD, 332 CAD patients exclude NAFLD and 338 health control subjects were determined by sequencing and polymerase chain reaction analysis. Relevant statistical methods were employed to analyze the genotypes, alleles and the clinical date. Inter-group differences and associations were assessed statistically using t-tests and Chi square and logistic analyses. The relative risk of AGTR1 rs3772622 for NAFLD was estimated by logistic regression analysis. Results: No significant difference in genotype and allele frequency of AGTR1 rs3772622 was found between the NAFLD without CAD population and the controls (P > 0.05). However, makeable difference was found when compared the CAD in patients with NAFLD and CAD free NAFLD patients (P < 0.001 OR = 2.09). Similarly, significant difference was found in AGTR1 rs3772622 genotype distribution between the groups of CAD patients and control (P = 0.046 OR = 1.71). Conclusions: AGTR1 rs3772622 gene polymorphism was not associated with the risk of NAFLD, but could increase the risk of NAFLD patients suffering from CAD in the Chinese Han population. Deeply mechanisms underlying the association between AGTR1 rs3772622 gene polymorphism and the risk of CAD in NAFLD patients need more research. © 2016 The Author(s).


Yuan C.,Nanjing Medical University | Lu L.L.,Digestive Disease Key Laboratory of Qingdao | Lu L.L.,Qingdao Municipal Hospital | An B.Q.,Nanjing Medical University | And 7 more authors.
Hepatitis Monthly | Year: 2015

Background: Recent genome-wide association studies (GWAS) identified that gene Lysophospholipase-like 1 (LYPLAL1) rs12137855 associated with non-alcoholic fatty liver disease (NAFLD). No research has been performed regarding the association between LYPLAL1 and NAFLD in China. Objectives: The aim of the present study was to investigate the association between the gene LYPLAL1 rs12137855 and NAFLD, and the effect on serum lipid profiles in a Chinese Han population. Patients and Methods: LYPLAL1 rs12137855 gene was genotyped in 184 patients with NAFLD and 114 healthy controls using sequencing and polymerase chain reaction analysis (PCR). We tested serum lipid profiles using biochemical methods. Results: No significant differences in genotype and allele frequencies of LYPLAL1 rs12137855 was found between the NAFLD group and the controls group (P > 0.05). Subjects with the variant LYPLAL1 rs12137855 CC genotype had a higher mean weight, body mass index (BMI) and low density lipoprotein (LDL). Conclusions: Our results showed for the first time that LYPLAL1 gene is not associated with a risk of NAFLD development in the Chinese Han population. The variant carriers of overall subjects significantly increased weight, BMI and LDL. © 2015 Kowsar Corp.


PubMed | Digestive Disease Key Laboratory of Qingdao, Qingdao Municipal Hospital and Dalian Medical University
Type: | Journal: Lipids in health and disease | Year: 2016

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease which represents a wide spectrum of hepatic damage. Several studies have reported that NAFLD is a strong independent risk factor for coronary artery disease (CAD). And patients with NAFLD are at higher risk and suggested undergoperiodic cardiovascular risk assessment. Cardiovascular disease (CVD) is responsible for the main cause of death in patients with NAFLD, and is mostly influenced by genetic factors. Both NAFLD and CAD are heterogeneous disease. Common pathways involved in the pathogenesis of NAFLD and CAD includes insulin resistance (IR), atherogenic dyslipidemia, subclinical inflammation, oxidative stress, etc. Genomic characteristics of these two diseases have been widely studied, further research about the association of these two diseases draws attention. The gene polymorphisms of adiponectin-encoding gene (ADIPOQ), leptin receptor (LEPR), apolipoprotein C3 (APOC3), peroxisome proliferator-activated receptors (PPAR), sterol regulatory elementbinding proteins (SREBP), transmembrane 6 superfamily member 2 (TM6SF2), microsomal triglyceride transfer protein (MTTP), tumor necrosis factors-alpha (TNF-) and manganese superoxide dismutase (MnSOD) have been reported to be related to NAFLD and CAD. In this review, we aimed to provide an overview of recent insights into the genetic basis of NAFLD and CAD.


PubMed | Digestive Disease Key Laboratory of Qingdao and Dalian Medical University
Type: | Journal: Lipids in health and disease | Year: 2015

Nonalcoholic fatty liver disease (NAFLD) is a metabolic stress-induced liver disease that is closely related not only to genetic susceptibility but also to insulin resistance and highly linked with metabolic syndrome. In recent years, the prevalence of NAFLD has increased rapidly, paralleling the epidemic of type 2 diabetes mellitus and obesity leading to cardiovascular disease. It has been demonstrated that NAFLD is highly associated with atherosclerosis. With recently gained knowledge, it appears that NAFLD may induce insulin resistance, dyslipidemia, oxidative stress, inflammation, and fluctuation of adipokines associated with atherosclerosis. In this review, we aimed to summarize recent discoveries related to both NAFLD and atherosclerosis, and to identify possible mechanisms linking them.


Chen L.,Qingdao University | Jiang M.,Digestive Disease Key Laboratory of Qingdao | Xin Y.,Qingdao University | Wang J.,Qingdao University | And 3 more authors.
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology | Year: 2016

OBJECTIVE: To investigate the role and mechanism of action of fibroblast growth factor-21 (FGF-21) in reducing triglyceride (TG) in the in vitro and in vivo models of nonalcoholic fatty liver disease (NAFLD).METHODS: (1) A mixture of free fatty acids was used to establish a model of steatosis in L02 cells, and the cells were treated with various concentrations of FGF-21 or fenofibrate. Twenty-four hours later, oil red O staining was performed to observe the degree of steatosis, and intracellular TG content was determined. RT-PCR and Western blot were applied to measure the mRNA and protein expression of sterol regulatory element-binding protein-1c (SREBP-1c). (2) High-fat diet was used to establish a mouse model of steatosis, and these mice were intraperitoneally injected with FGF-21 or fenofibrate. Eight weeks later, whole blood and liver samples were collected, and HE staining was performed to observe steatosis. Meanwhile, the serum levels of TG, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured, and TG content in the liver was also measured. One-way analysis of variance was used for comparison of data between multiple groups, and the least significant difference t-test was used for comparison between any two groups.RESULTS: (1) Compared with the control group, the model group showed significant steatosis, with significant increases in intracellular lipid droplets and TG content (t = -20.57, P < 0.01), while FGF-21 reduced the number of intracellular lipid droplets and TG content (F = 98.16, P < 0.01) in a dose-dependent manner. In addition, the model group had significantly increased mRNA and protein expression of SREBP-1c compared with the control group (t = -10.73 and -0.1006, both P < 0.01), while FGF-21 down-regulated the mRNA and protein expression of SREBP-1c (F = 161.35 and 36.72, both P < 0.01). (2) Compared with the mice in the control group, those in the model group showed significant steatosis and had significant increases in serum TG level and TG content in the liver (t = -18.84 and 15.71, both P < 0.01). FGF-21 relieved hepatic steatosis and reduced the serum TG level and TG content in the liver (t = 18.11 and 9.46, both P < 0.01). Moreover, FGF-21 reduced the serum levels of ALT and AST in NAFLD mice (t = 25.93 and 12.50, both P < 0.01).CONCLUSION: FGF-21 can inhibit the synthesis of TG through suppressing the expression of SREBP-1c, which further confirms the potential therapeutic effect of FGF-21 in the treatment of NAFLD. This may provide new ideas for the treatment of NAFLD.


PubMed | Digestive Disease Key Laboratory of Qingdao and Qingdao University
Type: Journal Article | Journal: Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology | Year: 2016

To investigate the role and mechanism of action of fibroblast growth factor-21 (FGF-21) in reducing triglyceride (TG) in the in vitro and in vivo models of nonalcoholic fatty liver disease (NAFLD).(1) A mixture of free fatty acids was used to establish a model of steatosis in L02 cells, and the cells were treated with various concentrations of FGF-21 or fenofibrate. Twenty-four hours later, oil red O staining was performed to observe the degree of steatosis, and intracellular TG content was determined. RT-PCR and Western blot were applied to measure the mRNA and protein expression of sterol regulatory element-binding protein-1c (SREBP-1c). (2) High-fat diet was used to establish a mouse model of steatosis, and these mice were intraperitoneally injected with FGF-21 or fenofibrate. Eight weeks later, whole blood and liver samples were collected, and HE staining was performed to observe steatosis. Meanwhile, the serum levels of TG, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured, and TG content in the liver was also measured. One-way analysis of variance was used for comparison of data between multiple groups, and the least significant difference t-test was used for comparison between any two groups.(1) Compared with the control group, the model group showed significant steatosis, with significant increases in intracellular lipid droplets and TG content (t = -20.57, P < 0.01), while FGF-21 reduced the number of intracellular lipid droplets and TG content (F = 98.16, P < 0.01) in a dose-dependent manner. In addition, the model group had significantly increased mRNA and protein expression of SREBP-1c compared with the control group (t = -10.73 and -0.1006, both P < 0.01), while FGF-21 down-regulated the mRNA and protein expression of SREBP-1c (F = 161.35 and 36.72, both P < 0.01). (2) Compared with the mice in the control group, those in the model group showed significant steatosis and had significant increases in serum TG level and TG content in the liver (t = -18.84 and 15.71, both P < 0.01). FGF-21 relieved hepatic steatosis and reduced the serum TG level and TG content in the liver (t = 18.11 and 9.46, both P < 0.01). Moreover, FGF-21 reduced the serum levels of ALT and AST in NAFLD mice (t = 25.93 and 12.50, both P < 0.01).FGF-21 can inhibit the synthesis of TG through suppressing the expression of SREBP-1c, which further confirms the potential therapeutic effect of FGF-21 in the treatment of NAFLD. This may provide new ideas for the treatment of NAFLD.


PubMed | Digestive Disease Key Laboratory of Qingdao and Nanjing Medical University
Type: Journal Article | Journal: Lipids in health and disease | Year: 2016

Recently genome-wide association studies identified that NCAN rs2228603 polymorphism was associated with non-alcoholic fatty liver disease (NAFLD) mainly in subjects of European ancestry. While no research have been conducted to demonstrate the relationship between NCAN rs2228603 and NAFLD in Chinese Han adults. The aim of this study was to investigate whether NCAN rs2228603 is associated with NAFLD in Chinese population.Gene NCAN rs2228603 was genotyped in 182 patients with NAFLD and 195 healthy controls. The expression of NCAN was tested according to polymerase chain reaction analysis (PCR) and serum lipids were performed by biology techniques.No significant difference was found in genotype and allele frequencies of NCAN rs2228603 between the NAFLD group and the controls (P>0.05). Subjects with the NCAN rs2228603 CT genotype showed a higher level of alkaline phosphatase (AKP) (P=0.017) and a higher high-density lipoprotein (HDL) (P<0.05).Our study for the first time identified that the gene NCAN rs2228603 is not a risk factor for the incidence of NAFLD in Chinese population. Also we found the dual and opposite role of T variant in protecting liver with a higher level of HDL and conferring risk for liver damage with a higher level of AKP.Chinese Clinical Trial Register.gov Identifier: ChiCTR-ROC-15006447 .

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