Nonalcoholic fatty liver disease (NAFLD) is a type of metabolic stress liver injury that is closely associated with insulin resistance and genetic susceptibility. The continuum of liver injury in NAFLD can range from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and even lead to cirrhosis and liver cancer. The pathogenesis of NAFLD is complicated. Pro-inflammatory cytokines, lipotoxicity, and gut bacterial metabolites play a key role in activating liver-resident macrophages (Kupffer cells, KCs) and recruiting circulating monocyte-derived macrophages (MoDMacs) to deposit fat in the liver. With the application of single-cell RNA-sequencing, significant heterogeneity in hepatic macrophages has been revealed, suggesting that KCs and MoDMacs located in the liver exert distinct functions in regulating liver inflammation and NASH progression. This study focuses on the role of macrophage heterogeneity in the development and occurrence of NAFLD and NASH, in view of the fact that innate immunity plays a key role in the development of NAFLD.
Humans ; Non-alcoholic Fatty Liver Disease/pathology* ; Liver/pathology* ; Macrophages/metabolism* ; Liver Cirrhosis/complications* ; Disease Progression

Non-alcoholic fatty liver disease (NAFLD) is a metabolic-related disorder induced by multiple factors and mainly characterized by excessive fat buildup in hepatocytes. With the consumption of a Western-style diet and obesity prevalence in recent years, the incidence of NAFLD has gradually increased, becoming an increasingly serious public health problem. Bilirubin is a heme metabolite and a potent antioxidant. Studies have demonstrated that bilirubin levels have an inverse correlation with the incidence rate of NAFLD; however, which form of bilirubin plays the main protective role is still controversial. It is considered that the main protective mechanisms for NAFLD are bilirubin antioxidant properties, insulin resistance reduction, and mitochondrial function. This article summarizes the correlation, protective mechanism, and possible clinical application of NAFLD and bilirubin.
Humans ; Non-alcoholic Fatty Liver Disease/metabolism* ; Bilirubin ; Antioxidants ; Obesity/complications* ; Hepatocytes/metabolism* ; Liver/metabolism*

BACKGROUNDAcute fatty liver of pregnancy (AFLP) is a rare but life-threatening complication occurring in the third trimester. It is often fatal to both mother and fetus. The complicated clinical manifestations as well as an insufficient understanding of the disease make the precise diagnosis and effective treatment of AFLP challenging. A full understanding of the risk factors, clinical features, and test findings of AFLP is critical for its timely diagnosis and treatment.

METHODSWe performed a retrospective study of 56 patients with AFLP between June 2008 and July 2013. We analyzed the clinical features, laboratory results, perioperative management, and patient outcomes.

RESULTSThe initial symptoms varied considerably, with nausea and vomiting (13/56, 23%) being the most common. Liver-function indexes were remarkable, including elevated levels of serum alanine aminotransferase (262.16 ± 281.71 U/L), aspartate aminotransferase (260.98 ± 237.91 U/L), lactic dehydrogenase (1011.76 ± 530.34 U/L), and direct bilirubin (85.59 ± 90.02 μmol/L). Coagulation disorders were indicated by abnormal levels of fibrinogen (245.95 ± 186.11 mg/dL), D-dimer (2.46 ± 4.01 mg/L), and fibrin degradation products (43.62 ± 48.71 mg/L). The main maternal complications were hypoproteinemia (75%), coagulopathy (54%), and acute renal failure (39%). Multivariate logistic regression analysis identified prothrombin time (PT; odds ratio [OR] = 1.558, 95% confidence interval [CI] =1.248-1.946, PORCIP= 0.009) as risk factors. The perinatal infant death rate was related to gestational age at delivery (ORCI PORCI PORCI PConclusions: Nausea and vomiting may be the most common symptoms of AFLP. Indexes of liver dysfunction and coagulation disorders should also be considered. PT and INR are risk factors for fatal complications in patients with AFLP, and perinatal mortality is linked to the level of fibrin degradation products. Timely delivery is crucial to controlling the development of AFLP.

Adolescent ; Adult ; Alanine Transaminase ; blood ; Aspartate Aminotransferases ; blood ; Bilirubin ; metabolism ; Fatty Liver ; blood ; metabolism ; pathology ; Humans ; L-Lactate Dehydrogenase ; metabolism ; Middle Aged ; Pregnancy Complications ; blood ; metabolism ; pathology ; Retrospective Studies ; Young Adult

PURPOSE: The severity of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) population compared with that in normal glucose tolerance (NGT) individuals has not yet been quantitatively assessed. We investigated the prevalence and the severity of NAFLD in a T2DM population using controlled attenuation parameter (CAP). MATERIALS AND METHODS: Subjects who underwent testing for biomarkers related to T2DM and CAP using Fibroscan® during a regular health check-up were enrolled. CAP values of 250 dB/m and 300 dB/m were selected as the cutoffs for the presence of NAFLD and for moderate to severe NAFLD, respectively. Biomarkers related to T2DM included fasting glucose/insulin, fasting C-peptide, hemoglobin A1c (HbA1c), glycoalbumin, and homeostasis model assessment of insulin resistance of insulin resistance (HOMA-IR). RESULTS: Among 340 study participants (T2DM, n=66; pre-diabetes, n=202; NGT, n=72), the proportion of subjects with NAFLD increased according to the glucose tolerance status (31.9% in NGT; 47.0% in pre-diabetes; 57.6% in T2DM). The median CAP value was significantly higher in subjects with T2DM (265 dB/m) than in those with pre-diabetes (245 dB/m) or NGT (231 dB/m) (all p<0.05). Logistic regression analysis showed that subjects with moderate to severe NAFLD had a 2.8-fold (odds ratio) higher risk of having T2DM than those without NAFLD (p=0.02; 95% confidence interval, 1.21-6.64), and positive correlations between the CAP value and HOMA-IR (ρ=0.407) or fasting C-peptide (ρ=0.402) were demonstrated. CONCLUSION: Subjects with T2DM had a higher prevalence of severe NAFLD than those with NGT. Increased hepatic steatosis was significantly associated with the presence of T2DM, and insulin resistance induced by hepatic fat may be an important mechanistic connection.
Adult ; Aged ; Biomarkers/metabolism ; C-Peptide/metabolism ; Case-Control Studies ; Diabetes Mellitus, Type 2/*complications/metabolism ; Female ; Hemoglobin A, Glycosylated/metabolism ; Humans ; Insulin Resistance ; Male ; Middle Aged ; Non-alcoholic Fatty Liver Disease/*epidemiology/metabolism/pathology ; Odds Ratio ; Prevalence

Whether nonalcoholic fatty liver disease (NAFLD) is related to vitamin D and bone health in obese children is unknown. The aim of this study was to evaluate vitamin D status and bone mineral density (BMD) in obese children according to their condition within the NAFLD spectrum. Anthropometric data, laboratory tests, and abdominal ultrasonography were obtained from 94 obese children. The subjects were divided into three groups according to NAFLD spectrum: normal liver, simple steatosis, and nonalcoholic steatohepatitis (NASH). Although there were no differences in vitamin D levels between the three groups, these groups showed significant differences in highly sensitive C-reactive protein (P=0.044), homeostasis model assessment of insulin resistance (HOMA-IR) (P=0.02), hepatic fibrosis scores (P<0.05), and trunk fat percentage (P=0.025). Although there were significant differences in BMDs, the age-matched BMD z-scores were not significantly different between the three groups. Serum vitamin D levels were negatively correlated with age (r=-0.368, P=0.023), serum uric acid levels (r=-0.371, P=0.022), fibrosis 4 (FIB4) (r=-0.406, P=0.011), and HOMA-IR (r=-0.530, P=0.001) in obese children with NASH. Multiple regression analysis for vitamin D in the NASH group revealed age and HOMA-IR as significant factors. In conclusion, inflammatory markers, hepatic fibrosis scores, trunk fat, and insulin resistance may reflect the spectrum of NAFLD in obese children, whereas vitamin D levels and BMD may not. In patients with NASH, however, low serum vitamin D is associated with hepatic fibrosis and insulin resistance, but not with bone health status.
Adolescent ; Adult ; Body Composition ; *Bone Density ; C-Reactive Protein/metabolism ; Child ; Female ; Humans ; Insulin Resistance ; Liver/pathology ; Male ; Non-alcoholic Fatty Liver Disease/*blood/*complications/pathology ; Obesity/*blood/*complications ; Regression Analysis ; Uric Acid/blood ; Vitamin D/*analogs & derivatives/blood ; Young Adult

OBJECTIVETo observe the effect of Zhenqing Recipe (ZQR) on non-alcoholic fatty liver (NAFL), and the expression of hepatic salt-inducible kinase 1 (SIK1) and sterol-regulatory element binding protein-ic (SREBP-lc) in type 2 diabetes rats.

METHODSA rat model of type 2 diabetes was established by high fat/sucrose diet combined with intraperitoneal injection of small dose streptozotocin (STZ) . Modeled rats were randomly divided into the model group, the ZQR group, and the metformin group, 8 in each group. Eight rats were recruited as a normal control group. ZQR at the daily dose of 12 g crude drugs/kg was administered to rats in the ZQR group by gastrogavage. Metformin suspension at the daily dose of 150 mg/kg was administered to rats in the metformin group by gastrogavage. Equal volume of distilled water was administered to rats in the normal control group and the model group. All medication lasted for 12 weeks. The levels of fasting blood glucose (FBG), free fatty acid (FFA), serum triglyceride (TG), serum total cholesterol (TC), serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were detected. The body weight and wet liver weight were weighed, and the liver weight index calculated. The liver TG content was measured. The pathological changes of liver and the expression of SIK1 were observed by HE staining and immunohistochemistry. The mRNA and protein expression of SIK1 and SREBP-1c were detected using RT-PCR and Western blot.

RESULTSCompared with the normal control group, FBG, FFA, TG, TC, ALT, AST, liver weight index, and liver TG contents significantly increased (P < 0.01); liver steatosis was severe, the mRNA and protein expression of SIK1 obviously decreased (P < 0.01); mRNA and protein expression of SREBP-1c increased (P < 0.01). After drug therapy, compared with the model group, FBG, FFA, TG, TC, ALT, AST, and liver weight index significantly decreased, liver TG contents significantly decreased, the mRNA and protein expression of SIK1 obviously increased, while mRNA and protein expression of SREBP-1c obviously decreased (P < 0.05, P < 0.01) in the ZQR group and the metformin group (P < 0.05, P < 0.01); and the pathological changes were also improved. All the indices were improved more in the ZQR group (all P < 0.05).

CONCLUSIONIn this experiment, we found that the expression of SIK1 decreased in NAFL rats with type 2 diabetes. ZQR could alleviate lesion of NAFL type 2 diabetes rats possibly by up-regulating hepatic SIK1 expression at mRNA and protein levels.

Animals ; Diabetes Mellitus, Type 2 ; complications ; drug therapy ; metabolism ; Disease Models, Animal ; Drugs, Chinese Herbal ; therapeutic use ; Fatty Liver ; complications ; drug therapy ; metabolism ; Liver ; metabolism ; Male ; Protein-Serine-Threonine Kinases ; metabolism ; Rats ; Rats, Wistar ; Sterol Regulatory Element Binding Protein 1 ; metabolism

OBJECTIVETo compare the effects of piglitazone and metformin on retinol-binding protein-4 (RBP-4) and adiponcetin (APN) in patients with type 2 diabetes mellitus (T2DM) complicated with Non alcohol fatty acid liver disease (NAFLD).

METHODSTotally 60 T2DM patients complicated with NAFLD were equally and randomly divided into pioglitazone group and metform group. The levels of biochemical indicators including body mass index (BMI), glucose hemoglobin A1C (GHbA1C), insulin resistance (HOMA-IR), fasting blood glucose (FBG), fasting insulin (FIns), and serum triglycerides (TG) as well as serum RBP-4 and APN level were measured pre-treatment and 12 weeks after treatments.

RESULTSAfter 12 weeks of treaments, BMI, FBG, HOMA-IR, GHbA1C, FIns, and TG decreased (all P<0.05) in both piglitazone group and metform group. APN increased (all P<0.05) in both groups. RBP-4 decreased (P<0.05) in piglitazone group. Compare with the metform group, the levels of RBP-4, FIns ,and HOMA-IR decreased and BMI increased in piglitazone group (P<0.05).

CONCLUSIONPiglitazone is superior to metoform in decreasing RBP-4 level and HOMA-IR in patients with T2DM complicated with NAFLD.

Adiponectin ; blood ; Adult ; Aged ; Diabetes Mellitus, Type 2 ; blood ; complications ; drug therapy ; Fatty Liver ; blood ; complications ; Female ; Humans ; Male ; Metformin ; pharmacology ; Middle Aged ; Retinol-Binding Proteins, Plasma ; metabolism ; Thiazolidinediones ; pharmacology

OBJECTIVETo compare and explore metabolic risk factors related to type 2 diabetes mellitus (T2DM) and the development of nonalcoholic fatty liver disease (NAFLD).

METHODSA total of 389 in-patients with T2DM (DM group, 204 cases) and T2DM with NAFLD (DM+NAFLD group, 185 cases) were enrolled in the study between October 2012 and July 2013. Clinical data collected for analysis included levels of blood lipids, liver function markers, uric acid (UA) and insulin, as well as results from the oral glucose tolerance test (OGTT) and C peptide releasing test. Improvements in insulin level, C peptide secretion index [HOMR-IR(CP)] and whole body insulin sensitivity index (ISIcomp) were used to estimate insulin sensitivity. Improvements in insulin level, C peptide secretion index [HOMR-islet(CP)], early insulin secretion index (delta I₃₀/delta G₃₀), correction of the islet beta cell function index (MBC1) and glucose disposition index (DI) were used to evaluate the function of pancreatic islet 1 beta cells. The t-test and repeated measures ANOVA were used for statistical analyses. Risk factors of T2DM with NAFLD were assessed by using logistic regression analysis.

RESULTSCompared with the DM group, the DM+NAFLD group had higher body mass index (BMI) and levels of triglycerides, alanine aminotransferase (ALT), aspartate aminotransferase, gamma glutamine transferase and UA (all P < 0.05), but lower age and level of high density lipoprotein cholesterol (both P < 0.05). Moreover, the DM+NAFLD group had higher postprandial blood glucose levels at 30 min (10.88 ± 2.87 mmol/L vs. 12.18 ± 2.79 mmol/L, t =-3.32), 60 min (14.65 ± 3.69 mmol/L vs. 15.99 ± 3.12 mmol/L, t =-3.46), 120 min (16.56 ± 5.11 mmol/L vs. 17.65 ± 4.29 mmol/L, t =-2.81) and 180 min (13.92 ± 5.10 mmol/L vs. 14.71 ± 4.91 mmol/L, t=-2.02) (all P < 0.05). The DM+NAFLD group had higher postprandial insulin levels at 60 min (28.62 ± 23.51 muIU/ml vs. 36.91 ± 33.47 aIU/ml, t =-3.46) and 120 min (36.36 ± 25.60 muIU/mL vs. 44.38 ± 34.95 muIU/mL, t =-3.35) (both P < 0.05). The DM+NAFLD group had higher postprandial C peptide levels at 30 min (2.74 ± 1.70 ng/mL vs. 4.30 ± 6.51 ng/ml, t =-4.97), 60 min (4.17+/-2.49 ng/ml vs. 5.19 ± 2.96 ng/ml, t =-3.29) and 120 min (6.08 ± 2.79 ng/ml vs. 6.76 ± 3.10 ng/ml, t =-2.19) (all P < 0.05). The DM+NAFLD group had higher HOMA-IR(CP) (1.505 ± 0.004 vs. 1.507 ± 0.005, t =-2.208, P less than 0.05), but lower ISIcomp (90.09+/-69.31 vs. 59.93 ± 24.52, t =5.608), MBCI (4.68 ± 4.31 vs. 3.83 ± 2.41, t =2.365) and DI (35.40 ± 71.83 vs. 15.37 ± 13.93, t =3.730) (all P < 0.05). Logistic analysis showed that BMI, ALT, postprandial level of C-peptide at 30 min, and UA were the major risk factors of T2DM with NAFLD (OR =1.208, 2.080, 1.041, and 1.005, respectively; all P < 0.05).

CONCLUSIONPatients with a propensity for developing nonalcoholic fatty liver disease may experience earlier open of type 2 diabetes. T2DM patients with NAFLD have more severe glucose metabolism disorders.

Adult ; Aged ; Aged, 80 and over ; Blood Glucose ; metabolism ; Diabetes Mellitus, Type 2 ; complications ; metabolism ; Female ; Humans ; Insulin ; blood ; Lipids ; blood ; Male ; Middle Aged ; Non-alcoholic Fatty Liver Disease ; complications ; metabolism ; Risk Factors

AIM: The potential of Trifolium pratense (red clover) extract in the prevention of lipid disorder has attracted increasing attention in recent years. In this study, the aim was to determine whether and how red clover extract affected the development of murine diet-induced non-alcoholic steatohepatitis. METHODS: Non-alcoholic steatohepatitis was induced in C57BL/6 mice by feeding mice with a methionine-choline-deficient (MCD) diet. Hematoxylin and eosin staining was used for histological analyses. Real-time PCR was used to analyze the mRNA expression levels. RESULTS: Hepatic steatosis and necroinflammation was observed in MCD diet-fed mice, and this diet-induced steatosis was significantly attenuated, whereas liver inflammation was not significantly attenuated, by red clover extract treatment. Consistent with the results of H&E staining, the MCD diet-induced increase of liver triglycerides and cholesterol levels were significantly reduced by red clover extract treatment. However, with the improvement in hepatic steatosis, mRNA levels of acetyl CoA oxidase, carnitine palmitoyl transferase-1, and liver fatty acid-binding protein, three genes regulated by peroxisome proliferator-activated receptor (PPAR) α, were unaffected. CONCLUSION Red clover extract alleviated MCD diet-induced hepatic steatosis, but did not ameliorate liver inflammation in C57BL/6 mice, and the improvement in hepatic steatosis was not through activating PPARα.
Animals ; Cholesterol ; metabolism ; Choline Deficiency ; complications ; Diet ; adverse effects ; Disease Models, Animal ; Inflammation ; drug therapy ; metabolism ; Liver ; drug effects ; metabolism ; Male ; Methionine ; deficiency ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease ; drug therapy ; etiology ; metabolism ; PPAR gamma ; metabolism ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; RNA, Messenger ; metabolism ; Trifolium ; Triglycerides ; metabolism

BACKGROUND/AIMS: The aims of this study were (1) to identify the useful clinical parameters of noninvasive approach for distinguishing nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver disease (NAFLD), and (2) to determine whether the levels of the identified parameters are correlated with the severity of liver injury in patients with NASH. METHODS: One hundred and eight consecutive patients with biopsy-proven NAFLD (age, 39.8+/-13.5 years, mean+/-SD; males, 67.6%) were prospectively enrolled from 10 participating centers across Korea. RESULTS: According to the original criteria for NAFLD subtypes, 67 patients (62.0%) had NASH (defined as steatosis with hepatocellular ballooning and/or Mallory-Denk bodies or fibrosis > or =2). Among those with NAFLD subtype 3 or 4, none had an NAFLD histologic activity score (NAS) below 3 points, 40.3% had a score of 3 or 4 points, and 59.7% had a score >4 points. Fragmented cytokeratin-18 (CK-18) levels were positively correlated with NAS (r=0.401), as well as NAS components such as lobular inflammation (r=0.387) and ballooning (r=0.231). Fragmented CK-18 was also correlated with aspartate aminotransferase (r=0.609), alanine aminotransferase (r=0.588), serum ferritin (r=0.432), and the fibrosis stage (r=0.314). A fragmented CK-18 cutoff level of 235.5 U/L yielded sensitivity, specificity, and positive and negative predictive values of 69.0%, 64.9%, 75.5% (95% CI 62.4-85.1), and 57.1% (95% CI 42.2-70.9), respectively, for the diagnosis of NASH. CONCLUSIONS: Serum fragmented CK-18 levels can be used to distinguish between NASH and NAFL. Further evaluation is required to determine whether the combined measurement of serum CK-18 and ferritin levels improves the diagnostic performance of this distinction.
Adult ; Aged ; Aged, 80 and over ; Alanine Transaminase/blood ; Asian Continental Ancestry Group ; Aspartate Aminotransferases/blood ; Biological Markers/blood ; Fatty Liver/classification/metabolism/*pathology ; Female ; Ferritins/blood ; Fibrosis/complications ; Humans ; Keratin-18/analysis ; Male ; Middle Aged ; Predictive Value of Tests ; Prospective Studies ; Republic of Korea ; Severity of Illness Index ; Young Adult