| BackgroundThe morbidity of nonalcoholic fatty liver (NAFLD) is rising gradually all over the world.However, the pathogenesis of NAFLD is not definite completely. It is said that cyclicrenin-angiotension system (RAS) and hepatic RAS are closely related to hepatic steatosis,hepatitis, hepatic fibrosis and cirrhosis. Renin (REN) is the first enzyme in RAS and productangiotensin II (ANG II) continuously by cascade reactions, so that ANG II promotes insulinresistance (IR), oxidative stress and inflammation. About the function of RAS activity onNAFLD, the researches were mainly cellular and animal experimentations, but the clinicaltrials were few. There were few reports about the influence of REN activity on NAFLD.Beside, there was no effective treatment on NAFLD. Some RAS inhibitors (such asangiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs))interposed NAFLD by a few cellular and animal experimentations, but there was fewresearches about the effects of renin inhibitor (RI) on NAFLD. Aliskiren is a kind of RI,could inhibit renin activity and RAS activity. Our trial was to investigate the relationshipbetween plasma renin activity (PRA) and NAFLD, and examine the therapeutic effect ofAliskiren on NAFLD in rats by high fat diet.Chapter I The relationship between plasma renin activity andnonalcoholic fatty liver diseaseObjectiveThe aim of the study was to investigate the clinical significance of plasma renin activity(PRA) in patients with nonalcoholic fatty liver disease (NAFLD). Methods350hospitalized patients and outpatients were divided into two groups, the NAFLD group(159cases) and the control group (191cases), determined by clinical diagnosis and theabdominal color dopolor ultrasonography and CT. The NAFLD patients were divided intotwo subgroups, the mild group and the moderate-severe group by the ratio of CT value ofliver and spleen. There is no difference about sex and age between the NAFLD group and thecontrol group. All patients’ medical histories were collected, and their plasma renin activity(PRA), angiotensin I (ANG II), angiotensin II (ANG II) were measured, as well as serumbiochemical parameters, such as transaminase, blood lipids, blood glucose. The associationbetween PRA and the occurrence and progress of NAFLD, and the relationship between PRAand serum biochemical parameter, were analyzed with SPSS17.0. The receiver operatorcharacteristic (ROC) analyses for PRA, Alanine aminotrasferase (ALT) were performed andcut-off value was determined in the progress of NAFLD.Results(1) The prevalence of NAFLD was different in a variety of age groups. The onset age ofNAFLD was mainly between51and80.(2) The proportion of NAFLD patients with Type2Diabetes mellitus (T2DM) or metabolicsyndrome (MS) was higher than that in the control group. The proportion of NAFLD patientswith T2DM was26.4%, whereas that in the control group was11.0%(P=0.000). Theproportion of NAFLD patients with MS was56.0%, whereas that in the control group was20.9%(P=0.000).(3) Compared with the control group, the levels of PRA, ANG I, ANG II, ALT, AST, GGT,TG, TC, Apo B, LDL-C, FBG were significantly higher in NAFLD group(P<0.05), whereasHDL-C was lower (P=0.000). The levels of PRA, ALT and GGT of the moderate-severegroup were highest (P=0.006;0.021;0.012), but the level of HDL-C of moderate-severegroup was the lowest (P=0.042).(4) Having T2DM or MS, PRA≥19pg/mL, ANG I≥1.06ng/mL, ANG II≥97pg/mL,ALT≥40U/L, GGT≥50U/L, TG≥1.70mmol/L, TC≥5.18mmol/L, HDL-C<0.9mmol/L(male)or <1.0mmol/L(female), LDL-C≥3.37mmol/L, FBG≥6.1mmol/L and2h PBG≥7.8mmol/L arerisk factors in the occurrence of NAFLD, especially having MS, PRA≥19pg/mL are key riskfactors (OR=5.940;2.671, P<0.05). Having MS, PRA≥19pg/mL and ALT≥40U/L are riskfactors in the progress of NAFLD, especially PRA≥19pg/mL and ALT≥40U/L are key riskfactors (OR=8.079;6.660, P<0.05). The rising of PRA (≥19pg/mL) is a key risk factor in occurrence and progress of NAFLD.(5) PRA were positively associated with the severity of NAFLD, ANG I, ANG II, ALT, GGT,TG, TC, LDL-C (r=0.276;0.674;0.756;0.203;0.272;0.172;0.144;0.130, P<0.05); PRAwas negatively correlated with HDL-C and the ratio of the liver and spleen(r=-0.163,-0.238,P<0.05).(6) During the ROC analyses for PRA and ALT for NAFLD patients, AUC of PRA was0.677(95%CI:0.577~0.777) with26.86pg/mL cut-off value. Its sensitivity was94.1%, which washigher than that in ALT, but its specificity was47.2%.ConclusionThe increasing concentration of PRA plays a significant role on the occurrence and progressof NAFLD.PRA was a more sensitive index for auxiliary assesses the severity and prognosisof NAFLD.Chapter II Therapeutic effects of renin inhibitor (Aliskiren) onnonalcoholic fatty liver disease in ratsObjectiveThe study examined the therapeutic effect of direct renin inhibitor (Aliskiren) onnonalcoholic fatty liver disease (NAFLD) in rats by high fat diet.Methods40healthy male Spraque-Dawley (SD) rats were completely randomly divided into threegroups: normal control group (group N, which was feed on normal diet,n=15), NAFLDmodel group (group M,n=15) and Aliskiren group (group A,n=10).Group M and group Awere feed high fat diet. Group A were given a gavage of Aliskiren (50mg/(kg·d)), whereasgroup N and group M receive a gavage of normal saline of the same volume with Aliskireneach for8weeks. Before the experiment test, the weight, height, systolic pressure (SP),diastolic pressure (DP) and fasting blood glucose (FBG) in the three groups were notdifferent, and those indexes of the three groups were recorded every week. At last,hematoxylin and eosin (HE) staining and oil red O staining under light microscopy was usedto observe liver histopathology. And factors including serum transaminase, blood lipids, FBG,insulin (INS), homeostasis model assessment-insulin resistance (HOMA-IR),malondialdehyde (MDA), plasma renin(REN), angiotensin II(ANG II), hepatic lipids, hepaticMDA, hepatic REN and ANG II, transforming growth factor β1(TGF-β1) were compared in the three groups and analyzed by SPSS17.0.Results(1) Compared with group N, the weight and Lee’s Index of rats in group M and group A werehigher, but those between group M and group A were not different. SP and DP of group Mwere highest in the three groups, whereas SP and DP of group A were lowest.(2) The hepatic weight and the hepatic index of group M were highest in the three groups, buthepatic weight and hepatic index between group M and group A were not different. ALT ingroup M was highest, whereas ALT of group was lower than that of group M. AST in groupM and group A were higher than that in group N. FBG, INS and HOMR-IR in group M andgroup A were higher than those in group N, but FBG, INS and HOMR-IR in group A werelower than those in group M.(3) Compared with group N, serum TG and TC in group M and group A were higher, butthose between group M and group A were not different. Hepatic lipids in group M and groupA were higher than those in group N, but hepatic lipids in group A were lower than those ingroup M. The serum MDA in group M was highest in the three groups, whereas serum MDAof group A was lower than that of group M. The hepatic MDA in group M and group A werehigher than group N, but hepatic MDA in group A was lower than those in group M.(4) REN and ANG II of plasma and liver in group M were highest in three groups, but RENand ANG II of plasma and liver in group A were lower than those in group M.(5) The hepatic TGF-β1of group M (TGF-β1=13.65±2.44ng/gprot) and group A(TGF-β1=11.51±2.82ng/gprot), whose rats were feed high fat diet, were higher than that ofgroup N (TGF-β1=6.99±1.01ng/gprot), but hepatic TGF-β1of group A was lower than that ofgroup M.(6) By means of HE staining and oil red O staining, Hepatocyte in all rats of group M andsome rats of group A had steatosis, but the degree of steatosis in group A was slighter thanthat in group M.ConclusionAliskiren attenuated the progression of NAFLD by suppressing RAS active (REN&ANG II)and by improving the insulin resistance (IR), lipid metabolism disorders and proinflammatorycytokine synthesis viz TGF-β1. |
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