• atrial fibrillation
• cardiovascular disease
• fibrosis
• inflammation
• metabolic dysfunction-associated steatotic liver disease
• metabolic syndrome
• nonalcoholic fatty liver disease

• ACE1
• ACE2
• Angiotensin
• Liver
• Metabolic syndrome
• Renin
• Vitamin D

• Humans
• Spironolactone/therapeutic use
• Spironolactone/pharmacology
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/epidemiology
• Non-alcoholic Fatty Liver Disease/metabolism
• Renin-Angiotensin System
• Mineralocorticoid Receptor Antagonists/therapeutic use
• Mineralocorticoid Receptor Antagonists/pharmacology

Losartan has become a hot spot in the treatment of non-alcoholic fatty liver disease (NAFLD) among angiotensin receptor blocker drugs. We sought to conduct a systematic examination and meta-analysis to examine the effects of losartan on patients with NAFLD. We searched for potentially randomized controlled trials in PubMed, Embase, China National Knowledge Infrastructure, Wanfang, and the Cochrane database up to October 09, 2022. We used the Cochrane risk of bias tool to evaluate the study quality. Analysis of subgroups, sensitivity analysis, and publishing bias were explored. The quality of the included studies was moderate to high. Six trials involving 408 patients were included. The meta-analysis demonstrated that aspartate transaminase was significantly affected by losartan therapy (mean difference [MD] = −5.34, 95% confidence interval [CI] [−6.54, −4.13], Z = 8.70, P < 0.01). The meta-analysis subgroup showed that losartan 50 mg once daily could lower the level of alanine aminotransferase (MD = −18.92, 95% CI [−21.18, −16.66], Z = 16.41, P < 0.01). There was no statistically significant difference in serum total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein.

• losartan
• liver function
• blood lipids
• non-alcoholic fatty liver disease

• chronic liver injury
• gene silencing
• handle region peptide
• lipid metabolism
• nonalcoholic fatty liver disease

• Aminobutyrates/therapeutic use
• Angiotensin Receptor Antagonists/therapeutic use
• Biphenyl Compounds/pharmacology
• Cholesterol
• Cross-Sectional Studies
• Drug Combinations
• Heart Failure/drug therapy
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Lipids
• Lipoproteins, HDL/pharmacology
• Retrospective Studies
• Stroke Volume
• Tetrazoles/therapeutic use
• Treatment Outcome
• Triglycerides
• Valsartan/pharmacology

• ARB, Insulin resistance
• Angiotensin receptor blocker
• Liver steatosis
• Metabolic syndrome
• NAFLD

• Angiotensin II Type 1 Receptor Blockers/pharmacology
• Animals
• Blood Glucose/metabolism
• Glucose/metabolism
• Insulin/metabolism
• Insulin Resistance
• Liver/metabolism
• Obesity/metabolism
• Rats
• Rats, Inbred OLETF
• Rats, Long-Evans
• Receptor, Angiotensin, Type 1/metabolism
• Triglycerides/metabolism

• chymase
• fibrosis
• inflammation
• inhibitor
• non-alcoholic steatohepatitis

• NLRP3-inflammasome
• adipose tissue angiogenesis
• mineralocorticoid receptor

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases. In this prospective study, we aim to explore the role of angiotensin II (Ang II) and NLRP3 inflammasome in NAFLD patients.

We prospectively enrolled 96 patients in our hospital from September 2014 to February 2016. Patients were divided into two groups (NAFLD group and Control group), and the serum Ang II level, IL-1β, IL-18, and lipids were analyzed. Correlation and multivariable analyses were used in order to identify the potential risk factors of NAFLD.

Although the two groups share a similar demographic background, the Ang II level of NAFLD group patients was significantly higher than that of the Control group (42.18 ± 12.37 vs. 36.69 ± 13.90, p = 0.014) when abdominal ultrasound was used for grouping. This finding was confirmed when a FibroScan Cap value was selected to divide participants into the NAFLD group and Control group (41.16 ± 13.06 vs. 34.85 ± 12.64, p = 0.040). Multivariable analysis showed that Ang II level is an independent risk factor of NAFLD whether abdominal ultrasound (OR = 1.056, p = 0.037) or FibroScan Cap value (OR = 1.069, p = 0.013) was deemed as the diagnostic standard. Furthermore, stepwise regression analysis was carried out between Ang II with other parameters and we discovered that Ang II had a linear correlation with IL-1β.

Ang II levels of NAFLD patients significantly increased, and elevated Ang II level is an independent risk factor of NAFLD. Our preliminary results also indicate that Ang II may promote the development of NAFLD by activating NLRP3 inflammasome.

Nonalcoholic fatty liver disease (NAFLD) is considered as a liver manifestation of metabolic disorders. Previous studies indicate that the renin-angiotensin system (RAS) plays a complex role in NAFLD. As the only precursor of the RAS, decreased angiotensinogen (AGT) profoundly impacts RAS bioactivity. Here, we investigated the role of hepatocyte-derived AGT in liver steatosis. AGT floxed mice (hepAGT^+/+) and hepatocyte-specific AGT-deficient mice (hepAGT^−/−) were fed a Western diet and a normal laboratory diet for 12 weeks, respectively. Compared with hepAGT^+/+ mice, Western diet-fed hepAGT^−/− mice gained less body weight with improved insulin sensitivity. The attenuated severity of liver steatosis in hepAGT^−/− mice was evidenced by histologic changes and reduced intrahepatic triglycerides. The abundance of SREBP1 and its downstream molecules, acetyl-CoA carboxylase and FASN, was suppressed in hepAGT^−/− mice. Furthermore, serum derived from hepAGT^+/+ mice stimulated hepatocyte SREBP1 expression, which could be diminished by protein kinase B (Akt)/mammalian target of rapamycin (mTOR) inhibition in vitro. Administration of losartan did not affect diet-induced body weight gain, liver steatosis severity, and hepatic p-Akt, p-mTOR, and SREBP1 protein abundance in hepAGT^+/+ mice. These data suggest that attenuation of Western diet-induced liver steatosis in hepAGT^−/− mice is associated with the alternation of the Akt/mTOR/SREBP-1c pathway.

• diet and diet lipids
• fatty acid/biosynthesis
• lipolysis and fatty acid metabolism
• nonalcoholic fatty liver disease
• nuclear receptor/Srebp
• triglycerides

Portal hypertension (PHT) resulting from splanchnic vasodilatation is a major cause of morbidity and mortality in patients with cirrhosis. The renin-angiotensin system (RAS) plays an important role in splanchnic vasodilatation in cirrhosis. This study investigated whether acute blockade of the vasodilatory receptors of the alternate RAS, Mas (MasR), Mas-related G-protein coupled receptor type D (MrgD), and angiotensin II type-2 receptor (AT2R) improves PHT in cirrhotic and non-cirrhotic portal hypertensive rats and counteracts systemic hypotension associated with angiotensin II type 1 receptor (AT1R) blockade. Cirrhotic bile duct ligated (BDL) or carbon tetrachloride (CCl₄) injected and non-cirrhotic partial portal vein ligated (PPVL) rats were used for measurement of portal pressure (PP) and mean arterial pressure before and after an intravenous bolus injection of the MasR, MrgD, and AT2R blockers, A779, D-Pro⁷-Ang-(1-7) (D-Pro) and PD123319, respectively. Separate groups of rats received a combined treatment with A779 or D-Pro given 20 min after AT1R blocker losartan. Mesenteric expression of MasR, MrgD, and AT2R and circulating levels of peptide blockers were also measured. Treatment with A779 and D-Pro significantly reduced PP in cirrhotic rat models. Despite rapid degradation of A779 and D-Pro in the rat circulation, the PP lowering effect of the blockers lasted for up to 25 min. We also found that PD123319 reduced PP in CCl₄ rats, possibly by blocking the MasR and/or MrgD since AT2R expression in cirrhotic mesenteric vessels was undetectable, whereas the expression of MasR and MrgD was markedly elevated. While losartan resulted in a marked reduction in PP, its profound systemic hypotensive effect was not counteracted by the combination therapy with A779 or D-Pro. In marked contrast, none of the receptor blockers had any effect on PP in non-cirrhotic PPVL rats whose mesenteric expression of MasR and MrgD was unchanged. We conclude that in addition to MasR, MrgD, a newly discovered receptor for Angiotensin-(1-7), plays a key role in splanchnic vasodilatation in cirrhosis. This implies that both MasR and MrgD are potential therapeutic targets to treat PHT in cirrhotic patients. We also conclude that the alternate RAS may not contribute to the development of splanchnic vasodilatation in non-cirrhotic PHT.

• Mas-related G-protein coupled receptor type D
• angiotensin II type 1 receptor
• cirrhosis
• mas receptor
• mesenteric vasculature
• portal hypertension
• portal pressure
• systemic hypotension

Irbesartan has shown significant therapeutic effects in hypertensive patients with non-alcoholic fatty liver disease (NAFLD). To determine the underlying mechanisms of its action, we established an in vitro model of NAFLD by treating human and mouse hepatocytes with free fatty acids (FFAs) and angiotensin (Ang) II. Irbesartan significantly reversed AngII/FFA-induced lipid deposition and mitochondrial dysfunction by restoring ATP production and the mitochondrial membrane potential (MMP), and decreasing the levels of reactive oxygen species (ROS) and inflammatory markers. In addition, irbesartan also increased the autophagy flux, in terms of increased numbers of autolysosomes and autophagosomes, and the upregulation and mitochondrial localization of the autophagic proteins Atg5 and LC3BII/I. Activation of protein kinase C (PKC) and inhibition of the autophagic flux exacerbated mitochondrial dysfunction in the steatotic hepatocytes. Furthermore, AngII upregulated PKC which inhibited AMPK phosphorylation via direct interaction with the AngII receptor AT1-R. Irbesartan inhibited PKC and activated AMPK and its downstream effector ULK1, thereby inducing autophagy, decreasing lipid deposition, and restoring mitochondrial function. Taken together, irbesartan triggers autophagy via the PKC/AMPK/ULK1 axis to ameliorate the pathological changes in the steatotic hepatocytes.

• AMPK
• PKC
• ULK1
• angiotensin II
• autophagy
• irbesartan
• lipid deposition

• Angiotensin II-forming activity
• Chymase
• Fatty liver
• Fib4 index
• Non-alcoholic steatohepatitis

• AGTR1 gene A1166C polymorphism
• Metabolic syndrome
• Non-alcoholic fatty liver disease
• Non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is characterized by inflammation and fibrosis, in addition to steatosis, of the liver, but no therapeutic agents have yet been established. The mast cell protease chymase can generate angiotensin II, matrix metalloproteinase-9 and transforming growth factor-β, all of which are associated with liver inflammation or fibrosis. In animal models of NASH, augmented chymase has been observed in the liver. In histological analysis, chymase inhibitor prevented hepatic steatosis, inflammation, and fibrosis. Chymase inhibitor also attenuated the augmentation of angiotensin II, matrix metalloproteinase-9, and transforming growth factor-β observed in the liver of NASH. Oxidative stress, inflammatory markers, and collagen were attenuated by chymase inhibition. Moreover, chymase inhibitor showed a mitigating effect on established NASH, and survival rates were significantly increased by treatment with chymase inhibitor. In this review, we propose that chymase inhibitor has potential as a novel therapy for NASH.

• angiotensin II
• chymase
• fibrosis
• inflammation
• inhibitor
• matrix metalloproteinase-9
• non-alcoholic steatohepatitis
• transforming growth factor-β

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, ranging from simple steatosis to progressive steatohepatitis and cirrhosis. Because of their anti-inflammatory and anti-fibrotic effects, angiotensin receptor blockers (ARBs) are potential therapeutic agents for NAFLD. The present systematic review assessed the effectiveness of ARBs in NAFLD management.

Accounting for data overlap and exclusion criteria, randomized controlled trial -based and single-arm meta-analyses were conducted for four studies with 362 patients and eight studies with 525 patients, respectively. Although alanine aminotransferase levels were not significantly affected by ARB treatment (standardized mean difference 0.20; 95% confidence interval (CI) [−0.04, 0.44]; P = 0.10), a fixed-effect model revealed a decreasing trend in alanine transaminase levels. Low-density lipoprotein levels were reduced by ARB treatment (MD 5.21; 95% CI [3.01, 7.40]; P < 0.00001), and total cholesterol also decreased in response to ARBs (MD 2.10; 95% CI [−0.37, 4.57]; P = 0.10). However, the fibrosis score and NAFLD activity score were not significantly improved by ARB treatment (MD 0.10; 95% CI [−0.58, 0.78]; P = 0.77) (MD −0.25; 95% CI [−1.05, 0.55]; P = 0.53).

Keywords were used to identify studies in PubMed, EMBASE, CENTRAL, Web of Science and CNKI published up to July 31, 2017. Single-arm and RCT-based meta-analyses of the available data were performed using RevMan (version 5.3).

Although ARBs significantly decreased plasma low-density lipoprotein and total cholesterol levels, the current evidence is insufficient to support the efficacy of ARBs in managing fibrosis in NAFLD patients.

• ARBs (angiotensin receptor blockers)
• NAFLD (non-alcoholic fatty liver disease)
• liver fibrosis
• liver inflammation
• meta-analysis

Non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) are common chronic non-infectious diseases with rising incidences. NAFLD is an independent risk factor for the onset of AF, after adjusting potentially related factors. The pathogenesis of these diseases share several mechanisms including reduced adiponectin level, insulin resistance, and renin angiotensin aldosterone system (RAAS) activation, in addition to activation of common disease pathways that promote inflammation, oxidative stress, and fibrosis. Furthermore, statins and RAAS blockers exert therapeutic effects concurrently on NAFLD and AF. The common pathogenesis of NAFLD and AF may serve as a potential therapeutic target in the future.

• adiponectin
• atrial fibrillation
• insulin resistance
• non-alcoholic fatty liver disease
• renin angiotensin aldosterone system

• Cell adhesion receptor
• Cell migration
• Liver fibrogenesis
• Matricellular protein
• Myofibroblasts

Aliskiren has been found to reduce chronic injury and steatosis in the liver of methionine-choline-deficient (MCD) diet-fed mice. This study investigated whether aliskiren has an anti-steatotic effect in HFD-fed mice, which are more relevant to human patients with non-alcoholic fatty liver disease than MCD mice. Mice fed with 4-week normal chow or HFD randomly received aliskiren (50 mg/kg/day) or vehicle via osmotic minipumps for further 4 weeks. Aliskiren reduced systemic insulin resistance, hepatic steatosis, epididymal fat mass and increased gastrocnemius muscle glucose transporter type 4 levels with lower tissue angiotensin II levels in the HFD-fed mice. In addition, aliskiren lowered nuclear peroxisome proliferator-activated receptor gamma and its down-signaling molecules and increased cytochrome P450 4A14 and carnitine palmitoyltransferase 1A (CPT1a) in liver. In epididymal fat, aliskiren inhibited expressions of lipogenic genes, leading to decrease in fat mass, body weight, and serum levels of leptin and free fatty acid. Notably, in the gastrocnemius muscle, aliskiren increased phosphorylation of insulin receptor substrate 1 and Akt. Based on these beneficial effects on liver, peripheral fat and skeletal muscle, aliskiren is a promising therapeutic agent for patients with NAFLD.

• Adipose tissue
• NEFA
• adipocyte
• angiotensin type 2 receptor
• high-fat/high-fructose diet
• insulin resistance

• Angiotensin-converting-enzyme inhibitors
• angiotensin receptor blocker
• liver fibrosis
• treatment

• Adolescent
• Adult
• Aged
• Angiotensin Receptor Antagonists/adverse effects
• Angiotensin Receptor Antagonists/pharmacology
• Angiotensin Receptor Antagonists/therapeutic use
• Biomarkers/metabolism
• Case-Control Studies
• Female
• Humans
• Liver Cirrhosis/drug therapy
• Male
• Middle Aged
• Renin-Angiotensin System/drug effects
• Young Adult

AIM: To investigate the roles of nuclear factor (NF)-κB and angiotensin II receptor type 1 (AT1R) in the pathogenesis of non-alcoholic fatty liver disease (NAFLD).

METHODS: Forty-two healthy adult male Sprague-Dawley rats were randomly divided into three groups: the control group (normal diet), the model group, and the intervention group (10 wk of a high-fat diet feeding, followed by an intraperitoneal injection of PDTC); 6 rats in each group were sacrificed at 6, 10, and 14 wk. After sacrifice, liver tissue was taken, paraffin sections of liver tissue specimens were prepared, hematoxylin and eosin (HE) staining was performed, and pathological changes in liver tissue (i.e., liver fibrosis) were observed by light microscopy. NF-κB expression in liver tissue was detected by immunohistochemistry, and the expression of AT1R in the liver tissue was detected by reverse transcription-polymerase chain reaction (RT-PCR). The data are expressed as mean ± SD. A two-sample t test was used to compare the control group and the model group at different time points, paired t tests were used to compare the differences between the intervention group and the model group, and analysis of variance was used to compare the model group with the control group. Homogeneity of variance was analyzed with single factor analysis of variance. H variance analysis was used to compare the variance. P < 0.05 was considered statistically significant.

RESULTS: The NAFLD model was successful after 6 wk and 10 wk. Liver fibrosis was found in four rats in the model group, but in only one rat in the intervention group at 14 wk. Liver steatosis, inflammation, and fibrosis were gradually increased throughout the model. In the intervention group, the body mass, rat liver index, serum lipid, and transaminase levels were not increased compared to the model group. In the model group, the degree of liver steatosis was increased at 6, 10, and 14 wk, and was significantly higher than in the control group (P < 0.01). In the model group, different degrees of liver cell necrosis were visible and small leaves, punctated inflammation, focal necrosis, and obvious ballooning degeneration were observed. Partial necrosis and confluent necrosis were observed. In the model group, liver inflammatory activity scores at 6, 10, and 14 wk were higher than in the control group (P < 0.01). Active inflammation in liver tissue in the intervention group was lower than in the model group (P < 0.05). HE staining showed liver fibrosis only at 14 wk in 4/6 rats in the model group and in 1/6 rats in the intervention group. NF-κB positive cells were stained yellow or ensemble yellow, and NF-κB was localized in the cytoplasm and/or nucleus. The model group showed NF-κB activation at 6, 10, and 14 wk in liver cells; at the same time points, there were statistically significant differences in the control group (P < 0.01). Over time, NF-κB expression increased; this was statistically lower (P < 0.05) at 14 weeks in the intervention group compared to the model group, but significantly increased (P < 0.05) compared with the control group; RT-PCR showed that AT1R mRNA expression increased gradually in the model group; at 14 wk, the expression was significantly different compared with expression at 10 weeks as well as at 6 weeks (P < 0.05). In the model group, AT1R mRNA expression was significantly higher than at the same time point in the control group (P < 0.01).

CONCLUSION: With increasing severity of NAFLD, NF-κB activity is enhanced, and the inhibition of NF-κB activity may reduce AT1R mRNA expression in NAFLD.

• Non-alcoholic fatty liver disease
• Nuclear factor-κB
• Angiotensin II receptor type 1
• Rats, Liver fibrosis

• Animals
• Diet, High-Fat
• Disease Progression
• Formates/pharmacology
• Liver/drug effects
• Liver/metabolism
• Liver/pathology
• Liver Cirrhosis, Experimental/metabolism
• Liver Cirrhosis, Experimental/pathology
• Male
• NF-kappa B/antagonists & inhibitors
• NF-kappa B/metabolism
• Necrosis
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/genetics
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/pathology
• RNA, Messenger/metabolism
• Rats, Sprague-Dawley
• Receptor, Angiotensin, Type 1/genetics
• Receptor, Angiotensin, Type 1/metabolism
• Severity of Illness Index
• Signal Transduction
• Time Factors

• GWAS
• Polymorphism
• SNP
• Steatosis

• ANG-(1–7)
• atherosclerosis
• lipodystrophy
• liver steatosis
• renin angiotensin system

• Animals
• Apolipoproteins E/deficiency
• Apolipoproteins E/genetics
• Apolipoproteins E/metabolism
• Atherosclerosis/metabolism
• Cholesterol/metabolism
• Fatty Liver/genetics
• Fatty Liver/metabolism
• Gene Knockout Techniques
• Genotype
• Lipids/blood
• Lipids/genetics
• Liver/metabolism
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Proto-Oncogene Mas
• Proto-Oncogene Proteins/genetics
• Proto-Oncogene Proteins/metabolism
• Receptors, G-Protein-Coupled/genetics
• Receptors, G-Protein-Coupled/metabolism

Activation of the renin-angiotensin-system is known to play a role in nonalcoholic steatohepatitis. Renin knockout mice manifest decreased hepatic steatosis. Aliskiren is the first direct renin inhibitor to be approved for clinical use. Our study aims to evaluate the possible therapeutic effects and mechanism of the chronic administration of aliskiren in a dietary steatohepatitis murine model.

Male C57BL/6 mice were fed with a methionine and choline-deficient (MCD) diet to induce steatohepatitis. After 8 weeks of feeding, the injured mice were randomly assigned to receive aliskiren (50 mg_·kg^-1 per day) or vehicle administration for 4 weeks. Normal controls were also administered aliskiren (50 mg_·kg^-1 per day) or a vehicle for 4 weeks.

In the MCD mice, aliskiren attenuated hepatic steatosis, inflammation and fibrosis. Aliskiren did not change expression of lipogenic genes but increase turnover of hepatic fat by up-regulating peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1a, cytochrome P450-4A14 and phosphorylated AMP-activated protein kinase. Furthermore, aliskiren decreased the hepatic expression of angiotensin II and nuclear factor κB. The levels of oxidative stress, hepatocyte apoptosis, activation of Kupffer cells and hepatic stellate cells, and pro-fibrotic markers were also reduced in the livers of the MCD mice receiving aliskiren.

Aliskiren attenuates steatohepatitis and fibrosis in mice fed with a MCD diet. Thus, the noted therapeutic effects might come from not only the reduction of angiotensin II but also the up-regulation of fatty acid oxidation-related genes.

• Amides/therapeutic use
• Angiotensin II/genetics
• Angiotensin II/metabolism
• Animals
• Blotting, Western
• Choline/metabolism
• Diet
• Fatty Liver/metabolism
• Fatty Liver/pathology
• Fatty Liver/prevention & control
• Fumarates/therapeutic use
• Immunoenzyme Techniques
• Inflammation/metabolism
• Inflammation/pathology
• Inflammation/prevention & control
• Insulin/genetics
• Insulin/metabolism
• Liver/metabolism
• Liver/pathology
• Male
• Methionine/deficiency
• Mice
• Mice, Inbred C57BL
• Oxidative Stress
• RNA, Messenger/genetics
• Real-Time Polymerase Chain Reaction
• Renin/antagonists & inhibitors
• Reverse Transcriptase Polymerase Chain Reaction
• Thiobarbituric Acid Reactive Substances/metabolism
• Triglycerides/metabolism

• Angiotensin II
• Fibrosis
• Mitochondria
• NAFLD
• Steatosis

• Angiotensin II/metabolism
• Animals
• Chronic Disease
• Fatty Liver/metabolism
• Fatty Liver/pathology
• Humans
• Insulin Resistance
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Metabolic Syndrome/metabolism
• Metabolic Syndrome/pathology
• Non-alcoholic Fatty Liver Disease
• Renin-Angiotensin System
• Signal Transduction

• T32 AR048523 NIAMS NIH HHS

• angiotensin II
• chymase
• fibrosis
• non-alcoholic steatohepatitis
• steatosis

• EGCG
• Hypertension
• Liver fibrosis
• Liver tumorigenesis
• Obesity

• angiotensina-(1–7)
• fatty liver
• lipid metabolism
• obesity
• visceral steatosis, congenital

• Administration, Oral
• Angiotensin I/administration & dosage
• Angiotensin I/pharmacology
• Animals
• Chemistry, Pharmaceutical
• Diet, High-Fat
• Fatty Liver/prevention & control
• Inflammation/prevention & control
• Interleukin-6/physiology
• Lipid Metabolism/drug effects
• Male
• Mice
• Peptide Fragments/administration & dosage
• Peptide Fragments/pharmacology
• Sterol Regulatory Element Binding Protein 1/physiology
• Tumor Necrosis Factor-alpha/physiology

Angiotensin II type 1 receptor (AGTR1) has been reported to play a fibrogenic role in non-alcoholic fatty liver disease (NAFLD). In this study, five variants of the AGTR1 gene (rs3772622, rs3772627, rs3772630, rs3772633, and rs2276736) were examined for their association with susceptibility to NAFLD. Subjects made up of 144 biopsy-proven NAFLD patients and 198 controls were genotyped using TaqMan assays. The liver biopsy specimens were histologically graded and scored according to the method of Brunt. Single locus analysis in pooled subjects revealed no association between each of the five variants with susceptibility to NAFLD. In the Indian ethnic group, the rs2276736, rs3772630 and rs3772627 appear to be protective against NAFLD (p = 0.010, p = 0.016 and p = 0.026, respectively). Haplotype ACGCA is shown to be protective against NAFLD for the Indian ethnic subgroup (p = 0.03). Gene-gene interaction between the AGTR1 gene and the patatin-like phospholipase domain-containing 3 (PNPLA3) gene, which we previously reported as associated with NAFLD in this sample, showed a strong interaction between AGTR1 (rs3772627), AGTRI (rs3772630) and PNPLA3 (rs738409) polymorphisms on NAFLD susceptibility (p = 0.007). Further analysis of the NAFLD patients revealed that the G allele of the AGTR1 rs3772622 is associated with increased fibrosis score (p = 0.003). This is the first study that replicates an association between AGTR1 polymorphism and NAFLD, with further details in histological features of NAFLD. There is lack of evidence to suggest an association between any of the five variants of the AGTR1 gene and NAFLD in the Malays and Chinese. In the Indians, the rs2276736, rs3772630 and rs3772627 appear to protect against NAFLD. We report novel findings of an association between the G allele of the rs3772622 with occurrence of fibrosis and of the gene-gene interaction between AGTR1gene and the much-studied PNPLA3 gene.

• Asian People
• Epistasis, Genetic/genetics
• Fatty Liver/ethnology
• Fatty Liver/genetics
• Genetic Predisposition to Disease/genetics
• Genotype
• Haplotypes/genetics
• Humans
• Linkage Disequilibrium
• Lipase/genetics
• Logistic Models
• Membrane Proteins/genetics
• Non-alcoholic Fatty Liver Disease
• Polymorphism, Single Nucleotide/genetics
• ROC Curve
• Receptor, Angiotensin, Type 1/genetics
• Statistics, Nonparametric
• White People

• Angiotensin-Converting Enzyme Inhibitors/pharmacology
• Animals
• History, 20th Century
• Humans
• Peptidyl-Dipeptidase A/chemistry
• Peptidyl-Dipeptidase A/history
• Peptidyl-Dipeptidase A/physiology
• Polymorphism, Genetic
• Protein Structure, Tertiary
• Renin/physiology

• T32 DK007770 NIDDK NIH HHS
• T32DK007770 NIDDK NIH HHS
• R01 HL110353 NHLBI NIH HHS
• R00 DK083455 NIDDK NIH HHS
• F32H105036 PHS HHS
• R00DK083455 NIDDK NIH HHS
• R01HL110353 NHLBI NIH HHS

• Coronary Artery Disease/etiology
• Diabetes Mellitus, Type 2/etiology
• Humans
• Metabolic Syndrome/complications
• Metabolic Syndrome/diagnosis
• Metabolic Syndrome/epidemiology
• Metabolic Syndrome/pathology
• Prevalence

• Angiotensin II/metabolism
• Angiotensin Receptor Antagonists/chemistry
• Angiotensin Receptor Antagonists/pharmacology
• Animals
• Cardiovascular Agents/pharmacology
• Cardiovascular Diseases/drug therapy
• Cardiovascular Diseases/genetics
• Cardiovascular Diseases/metabolism
• Drug Discovery/methods
• Female
• Humans
• Pregnancy
• Receptors, Angiotensin/biosynthesis
• Receptors, Angiotensin/genetics
• Receptors, Angiotensin/metabolism

• HL82779 NHLBI NIH HHS
• HL83966 NHLBI NIH HHS
• HD31226 NICHD NIH HHS
• R01 HL089012 NHLBI NIH HHS
• R01 HL082779 NHLBI NIH HHS
• P01 HD031226 NICHD NIH HHS
• HL89012 NHLBI NIH HHS
• R01 HL083966 NHLBI NIH HHS
• R01 HL110125 NHLBI NIH HHS

• Animals
• Body Weight/physiology
• Humans
• Insulin/metabolism
• Metabolic Syndrome/metabolism
• Metabolic Syndrome/physiopathology
• Renin-Angiotensin System/physiology

• F31 NS068122 NINDS NIH HHS
• K99 HL096830 NHLBI NIH HHS
• R00 HL096830 NHLBI NIH HHS
• R01 DK078201 NIDDK NIH HHS

• Animals
• Body Weight/drug effects
• Cells, Cultured
• Dietary Carbohydrates/administration & dosage
• Dietary Fats/administration & dosage
• Fatty Liver/metabolism
• Fatty Liver/prevention & control
• Gene Expression/drug effects
• Gluconeogenesis/drug effects
• Glucose/metabolism
• Hep G2 Cells
• Humans
• Inflammation/genetics
• Inflammation/metabolism
• Inflammation/prevention & control
• Insulin/blood
• Lipid Metabolism/drug effects
• Lipids/blood
• Male
• Mice
• Mice, Inbred C57BL
• Mineralocorticoid Receptor Antagonists/pharmacology
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction
• Spironolactone/pharmacology
• Trans-Activators/genetics
• Transcription Factors