Effect of phospholipid curcumin Meriva® on liver histology and kidney disease in nonalcoholic steatohepatitis a randomized, double-blind, placebo-controlled trial.

BACKGROUND AIMS: Nonalcoholic steatohepatitis (NASH) confers an increased liver-related and kidney morbidity. Phospholipid curcumin (Meriva ® ) is a phospholipid formulation with ameliorated systemic curcumin absorption and delivery. We assessed safety and efficacy of Meriva ® in NASH. APPROACH: In this double-blind trial, 52 biopsy-proven NASH patients(71% with stage ≥F2 fibrosis, 58% with stage A2-G2/A2-G3a CKD) were randomized 1:1 to receive Meriva ® 2 g/day or placebo for 72 weeks. Primary end-point was NASH resolution with no worsening of fibrosis. Secondary end-points included: a ≥1 stage liver fibrosis improvement with no NASH worsening; regression of significant(i.e. stage≥F2) fibrosis and of chronic kidney disease(CKD); improvement in renal, glucose, lipid and inflammatory parameters. We also explored treatment effect on hepatic activation of Nuclear Factor(NF)-kB, a key proinflammatory transcription factor and a major target of curcumin. RESULTS: Fifty-one patients(26 on Meriva ® and 25 on placebo) completed the trial. Sixteen(62%) patients on Meriva ® vs. three(12%) patients on placebo had NASH resolution(RR=5.33[95%CI=1.76-12.13]; p=0.003). Thirteen(50%) patients on Meriva ® vs. 2(8%) patients on placebo had ≥1 stage fibrosis improvement(RR=6.50[(1.63-21.20]; p=0.008). Eleven(42%) patients on Meriva ® vs. 0(0%) on placebo had regression of significant liver fibrosis(RR=18.01[1.43-36.07]; p=0.02). Hepatic NF-kB inhibition predicted NASH resolution(AUC=0.90,95%CI=0.84-0.95) and fibrosis improvement(AUC=0.89,95%CI=0.82-0.96). Thirteen(50%) patients on Meriva ® vs. 0(0%) on placebo had CKD regression(RR=10.71[1.94-17.99)]; p=0.004). Compared with placebo, Meriva ® improved eGFR(difference in adjusted eGFR change: +3.59[2.96-4.11] mL/min/1.73 m 2 /year, p =0.009), fasting glucose(-17 mg/dL;95%CI=-22, -12), HbA1c(-0.62%;95%CI=-0.87%, -0.37%), LDL-C(-39 mg/dL; 95%CI=-45, -33), triglycerides(-36 mg/dL, 95%CI= -46, -26), HDL-C(+10 mg/dL; 95%CI=+8, +11) and inflammatory markers. Adverse events were rare, mild and evenly distributed. CONCLUSION: In NASH patients, Meriva ® administration for 72 weeks was safe, well-tolerated, improved liver histology, possibly through NF-kB inhibition, kidney disease, and metabolic profile.

Endoscopic duodenal mucosa ablation techniques for diabetes and nonalcoholic fatty liver disease: A systematic review.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is increasing at an alarming rate, and only 50% of patients with T2DM achieve or maintain adequate glycemic control with pharmacological therapies. Metabolic surgery demonstrated superior efficacy compared to medical therapy but is unfeasible for most patients with T2DM. Duodenal mucosal resurfacing (DMR) by hydrothermal mucosal ablation, recellularization via electroporation therapy (ReCET), and photodynamic therapy are novel endoscopic procedures that use thermal, electrical, and photochemical energy, respectively, to ablate and reset dysfunctional duodenal mucosa. We assessed the data on the effects of these techniques on glycemic control and nonalcoholic fatty liver disease (NAFLD). METHODS: We systematically searched independently and in duplicate English and non-English language publications through January 31st, 2024. Outcomes assessed were an improvement in different metabolic health parameters and the safety of duodenal mucosal ablation (DMA) procedures. Outcomes were presented descriptively. FINDINGS: We selected 12 reports reporting results from 3 randomized and 6 uncontrolled trials (seven evaluating DMR, two evaluating ReCET, all with a low risk of bias) for a total of 317 patients enrolled. DMA reduced HbA1c, fasting plasma glucose, and liver fat. When combined with newer antidiabetic drugs, it allowed insulin discontinuation in up to 86% patients. No major safety signal emerged. CONCLUSIONS: All DMA techniques improve glucose homeostasis; DMR and ReCET appear to be safe in patients with T2DM. If confirmed by future randomized trials and by trials with histological endpoints in NAFLD, then DMA appears to be a promising alternative or complement option to medications for T2DM and NAFLD treatment. FUNDING: This study received no funding.

An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease.

Background: With the rising global prevalence of fatty liver disease related to metabolic dysfunction, the association of this common liver condition with chronic kidney disease (CKD) has become increasingly evident. In 2020, the more inclusive term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to replace the term non-alcoholic fatty liver disease (NAFLD). The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD. However, to date, there is no appropriate guidance on CKD in individuals with MAFLD. Furthermore, there has been little attention paid to the link between MAFLD and CKD in the Nephrology community. Methods and Results: Using a Delphi-based approach, a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD. Conclusions: This Delphi-based consensus statement provided guidance on the epidemiology, mechanisms, management and treatment of MAFLD and CKD, as well as the relationship between the severity of MAFLD and risk of CKD, which establish a framework for the early prevention and management of these two common and interconnected diseases.

Recent Insight into the Role of Fibrosis in Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world and its prognosis is poor because of lack of effective treatments. Epidemiological studies show that non-alcoholic steatohepatitis (NASH) and advanced fibrosis represent a relevant risk factors to the HCC development. However little is known of pathophysiological mechanisms linking liver fibrogenesis to HCC in NASH. Recent advances in scientific research allowed to discover some mechanisms that may represent potential therapeutic targets. These include the integrin signaling, hepatic stellate cells (HSCs) activation, Hedgehog signaling and alteration of immune system. In the near future, knowledge of fibrosis-dependent carcinogenic mechanisms, will help optimize antifibrotic therapies as an approach to prevent and treat HCC in patients with NASH and advanced fibrosis.

Angiotensin II Type 1 Receptor rs5186 Gene Variant Predicts Incident NAFLD and Associated Hypertension: Role of Dietary Fat-Induced Pro-Inflammatory Cell Activation.

OBJECTIVES: Hypertension has been linked to the presence and severity of nonalcoholic fatty liver disease (NAFLD) through unclear mechanisms. The gain-of-function rs5186 A1166C variant in angtiotensin receptor type 1 (AGTR1) gene has been linked to hypertension, cardiovascular disease and metabolic syndrome. We assessed the impact of AGTR1 A1166C variant on NAFLD incidence and severity and on glucose and lipid metabolism and explored the underlying mechanisms. METHODS: We followed up 314 healthy nonobese, nondiabetic, nonhypertensive, insulin-sensitive participants in a population-based study, characterized for AGTR1 rs5186 A1166C variant, adipokine profile, inflammatory and endothelial dysfunction markers. An independent cohort of 78 biopsy-proven nondiabetic NAFLD patients and controls underwent an oral glucose tolerance test with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, calprotectin, and nuclear factor-κB activation in circulating mononuclear cells. RESULTS: AGTR1 A1166C polymorphism predicted 9.8-year incident NAFLD (odds ratio: 1.67, 95% CI: 1.26-2.21) and hypertension (odds ratio: 1.49, 95% CI: 1.12-2.63) and 9-year increase in cardiovascular disease risk and endothelial dysfunction markers. In the cross-sectional cohort, AGTR1 C allele carriers had higher insulin resistance. Despite comparable fasting lipid profiles, AGTR1 C allele carriers showed postprandial triglyceride-rich and cholesterol-rich VLDL lipoprotein accumulation, higher resistin, MCP-1 and calprotectin responses and nuclear factor-κB activation in mononuclear cells, and a blunted postprandial adiponectin response to fat, which predicted liver histology, hepatocyte apoptosis activation, insulin resistance, and endothelial dysfunction. DISCUSSION: AGTR1 A1166C variant affects liver disease, insulin resistance, and endothelial dysfunction in NAFLD, at least in part by modulating adipokine, chemokine, and pro-inflammatory cell activation in response to fat ingestion.

TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD.

Mechanisms underlying the opposite effects of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (NAFLD) are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese nondiabetic normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry; an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis. The TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, impaired pancreatic ß-cell function and incretin effect, and higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with the TM6SF2 C-allele, the T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, and a postprandial cholesterol (Chol) redistribution from smaller atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfractions. Postprandial plasma VLDL1-Chol response independently predicted the severity of liver histology. In conclusion, the TM6SF2 C>T polymorphism affects nutrient oxidation, glucose homeostasis, and postprandial lipoprotein, adipokine, and GIP responses to fat ingestion independently of fasting values. These differences may contribute to the dual and opposite effect of this polymorphism on liver injury and cardiometabolic risk in NAFLD.

MERTK rs4374383 variant predicts incident nonalcoholic fatty liver disease and diabetes: role of mononuclear cell activation and adipokine response to dietary fat.

The loss-of-function rs4374383 G > A variant in Myeloid-epithelial-reproductive Tyrosine Kinase (MERTK) gene has been linked to hepatic fibrosis in chronic liver diseases. MERTK is expressed by immune and non-immune cells involved in inflammation, metabolism and vascular homeostasis. We assessed the impact of MERTK rs4374383 G > A variant on nonalcoholic fatty liver disease (NAFLD) incidence and severity and on glucose and lipid metabolism. We followed-up 305 healthy nonobese nondiabetic, metabolic syndrome-free insulin sensitive participants in a population-based study, characterized for MERTK G > A polymorphism, adipokine profile and inflammatory markers.An independent cohort of 69 biopsy-proven nondiabetic NAFLD patients and 69 healthy controls underwent indirect calorimetry, an OGTT with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, and of Nuclear Factor (NF)-κB activation in circulating mononuclear cells (MNCs). In the longitudinal cohort, MERTK G > A polymorphism protected against 9-year incident NAFLD (OR:0.48,95%CI:0.26-0.79) and diabetes (OR: 0.47, 95% CI: 0.19-0.87).In the cross-sectional cohort, MERTK A-allele carriers had higher fat oxidation rates and tissue insulin sensitivity. Despite comparable fastign and postprandial lipid profiles, MERTK A-allele carriers showed lower resistin and MCP-1 responses, milder MNC NF-κB activation, and a higher postprandial adiponectin response to fat, which predicted tissue insulin resistance hepatocyte apoptosis and liver histology. MERTK G > A variant affects liver disease, nutrient oxidation and glucose metabolism in NAFLD. The modulation of adipokine, chemokine and pro-inflammatory MNC activation in response to fat ingestion may contribute to the observed effects on liver and metabolic disease.

Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis: A Meta-analysis.

Importance: Nonalcoholic steatohepatitis (NASH) is projected to be the leading cause of liver transplantation by 2020. Advanced fibrosis (stage F3-F4) on liver biopsy independently predicts all-cause and liver-related mortality in NASH. There are no known efficacious treatments for advanced fibrosis related to NASH. Thiazolidinedione therapy has been extensively evaluated in NASH, and new randomized clinical trials (RCTs) of its efficacy have been completed. Objective: To synthesize the evidence about the association of thiazolidinedione therapy with advanced liver fibrosis in NASH. Data Sources: MEDLINE, Ovid MEDLINE In-Process, Cochrane Library, EMBASE, clinicaltrials.gov, PubMed, and Scopus databases (without language restrictions), as well as other registries and scientific meeting presentations, from database inception through August 15, 2016. Study Selection: Randomized clinical trials evaluating the effect of thiazolidinedione therapy on histologic features of the liver in biopsy-proven NASH. Data Extraction and Synthesis: Two investigators extracted study data independently and in duplicate and rated the risk of bias using the Cochrane Risk of Bias Tool. Main Outcomes and Measures: The primary outcome was a dichotomous improvement in advanced fibrosis on liver biopsy, defined as an improvement in fibrosis stage from F3-F4 to F0-F2. Secondary outcomes were at least a 1-point improvement in fibrosis of any stage and NASH resolution. This meta-analysis also evaluated adverse effects of thiazolidinedione therapy, including weight gain, lower limb edema, congestive heart failure, bone fractures, cancer, and anemia. With the use of random-effects models, dichotomous variables are presented as odds ratios (ORs) with 95% CIs, and continuous variables are presented as weighted mean differences with 95% CIs. Results: This study analyzed 8 RCTs (5 evaluating pioglitazone use and 3 evaluating rosiglitazone maleate use) enrolling 516 patients with biopsy-proven NASH for a duration of 6 to 24 months. Among all studies combined, thiazolidinedione therapy was associated with improved advanced fibrosis (OR, 3.15; 95% CI, 1.25-7.93; P = .01; I2 = 0%), fibrosis of any stage (OR, 1.66; 95% CI, 1.12-2.47; P = .01; I2 = 0%), and NASH resolution (OR, 3.22; 95% CI, 2.17-4.79; P < .001; I2 = 0%). Analyses restricted to RCTs enrolling patients without diabetes yielded similar results for improvement in advanced fibrosis (OR, 2.95; 95% CI, 1.04-10.90; P = .02; I2 = 0%), improvement in fibrosis of any stage (OR, 1.76; 95% CI, 1.02-3.03; P = .02; I2 = 0%), and NASH resolution (OR, 3.40; 95% CI, 1.95-5.93; P < .001; I2 = 0%). All effects were accounted for by pioglitazone use. Weight gain and lower limb edema occurred more frequently with thiazolidinedione therapy (initial body weight +2.70%; 95% CI, 1.96%-4.34%; P = .001). The small sample size of included RCTs prevented evaluation of more serious adverse effects of thiazolidinedione therapy. Conclusions and Relevance: Pioglitazone use improves advanced fibrosis in NASH, even in patients without diabetes. Whether this finding translates to improvement in risk for clinical outcomes requires further study.

Altered gut-liver axis and hepatic adiponectin expression in OSAS: novel mediators of liver injury in paediatric non-alcoholic fatty liver.

BACKGROUND: Mechanism(s) connecting obstructive sleep apnoea syndrome (OSAS) to liver injury in paediatric non-alcoholic fatty liver disease (NAFLD) are unknown. We hypothesised alterations in gut-liver axis and in the pool and phenotype of hepatic progenitor cells (HPCs) may be involved in OSAS-associated liver injury in NAFLD. METHODS: Eighty biopsy-proven NAFLD children (age, mean±SD, 11.4±2.0 years, 56% males, body mass index z-score 1.95±0.57) underwent a clinical-biochemical assessment, with measurement of insulin sensitivity, plasma cytokines, lipopolysaccharide (LPS), an intestinal permeability test and a standard polysomnography. Hepatic toll-like receptor (TLR)-4 expression by liver-resident cells and overall number and expression of resistin and adiponectin by HPCs were assessed by immunofluorescence and immunohistochemistry. OSAS was defined by an apnoea/hypopnoea index ≥1. RESULTS: OSAS was characterised by an increased intestinal permeability and endotoxemia, coupled with TLR-4 upregulation in hepatocytes, Kupffer and hepatic stellate cells (HSCs) and by an expansion of an adiponectin-deficient HPC pool, key features of steatohepatitis and fibrosis.The duration of haemoglobin desaturation (SaO2 <90%) independently predicted intestinal permeability (ß: 0.396; p=0.026), plasma LPS (ß: 0.358; p=0.008) and TLR-4 expression by hepatocytes (ß: 0.332; p=0.009), Kupffer cells (ß: 0.357; p=0.006) and HSCs (ß:0.445; p=0.002).SaO2 <90% predicted also HPC number (ß: 0.471; p=0.001) and impaired adiponectin expression by HPC pool (ß: -0.532; p=0.0009).These relationships were observed in obese and non-obese children. CONCLUSIONS: In paediatric NAFLD, OSAS is associated with increased endotoxemia coupled with impaired gut barrier function, with increased TLR-4-mediated hepatic susceptibility to endotoxemia and with an expansion of an adiponectin-deficient HPC pool. These alterations may represent a novel pathogenic link and a potential therapeutic target for OSAS-associated liver injury in NAFLD.

OSAS-related inflammatory mechanisms of liver injury in nonalcoholic fatty liver disease.

Obstructive sleep apnoea syndrome (OSAS) is a common sleep disorder, affecting over 4% of the general population, and is associated with metabolic syndrome and cardiovascular disease, independent of obesity and traditional risk factors. OSAS has been recently connected to nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the world, which can be found in 30% of the general adult population. Several studies suggest that the chronic intermittent hypoxia (CIH) of OSAS patients may per se trigger liver injury, inflammation, and fibrogenesis, promoting NAFLD development and the progression from steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. In NAFLD patients, liver disease may be caused by hypoxia both indirectly by promoting inflammation and insulin resistance and directly by enhancing proinflammatory cytokine production and metabolic dysregulation in liver cells. In this review, we focus on molecular mechanisms linking OSAS to NAFLD, including hypoxia inducible factor (HIF), nuclear factor kappa B (NF-κB), YKL-40, unfolded protein response, and hypoxic adipose tissue inflammation, which all could provide novel potential therapeutic approaches for the management of NAFLD patients with OSAS.

Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance.

RATIONALE: Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are frequently encountered in obese children. Whether OSAS and intermittent hypoxia are associated with liver injury in pediatric NAFLD is unknown. OBJECTIVES: To assess the relationship of OSAS with liver injury in pediatric NAFLD. METHODS: Sixty-five consecutive children with biopsy-proven NAFLD (age, mean ± SD, 11.7 ± 2.1 yr; 58% boys; body mass index z score, 1.93 ± 0.61) underwent a clinical-biochemical assessment and a standard polysomnography. Insulin sensitivity, circulating proinflammatory cytokines, markers of hepatocyte apoptosis (cytokeratin-18 fragments), and hepatic fibrogenesis (hyaluronic acid) were measured. Liver inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3, and CD163, surface markers of leukocytes, T cells, and activated macrophage/Kupffer cells, respectively. OSAS was defined by an apnea/hypopnea index (AHI) greater than or equal to 1 event/h, and severe OSAS was defined by an AHI greater than or equal to 5 events/h. MEASUREMENTS AND MAIN RESULTS: Fifty-five percent of children with NAFLD had nonalcoholic steatohepatitis (NASH), and 34% had significant (stage F ≥ 2) fibrosis. OSAS affected 60% of children with NAFLD; the presence and severity of OSAS were associated with the presence of NASH (odds ratio, 4.89; 95% confidence interval, 3.08-5.98; P = 0.0001), significant fibrosis (odds ratio, 5.91; 95% confidence interval, 3.23-7.42; P = 0.0001), and NAFLD activity score (ß, 0.347; P = 0.029), independently of body mass index, abdominal adiposity, metabolic syndrome, and insulin resistance. This relationship held also in nonobese children with NAFLD. The duration of hemoglobin desaturation (Sa(O2) < 90%) correlated with increased intrahepatic leukocytes and activated macrophages/Kupffer cells and with circulating markers of hepatocyte apoptosis and fibrogenesis. CONCLUSIONS: In pediatric NAFLD, OSAS is associated with biochemical, immunohistochemical, and histological features of NASH and fibrosis. The impact of hypoxemia correction on liver disease severity warrants evaluation in future trials.

Impact of sterol regulatory element-binding factor-1c polymorphism on incidence of nonalcoholic fatty liver disease and on the severity of liver disease and of glucose and lipid dysmetabolism.

BACKGROUND: Genetic factors that predispose individuals to nonalcoholic fatty liver disease (NAFLD) and associated diabetes and cardiovascular disease are unclear. The transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) modulates lipogenesis and insulin sensitivity and was experimentally connected to NAFLD. OBJECTIVE: We assessed the impact of a common SREBF-1c polymorphism on the incidence and severity of NAFLD and on associated glucose and lipoprotein dysmetabolism. DESIGN: We followed up 212 randomly selected, nonobese, nondiabetic, insulin-sensitive participants in a population-based study without NAFLD or metabolic syndrome at baseline who were characterized for the common SREBF-1c gene rs11868035 A/G polymorphism, dietary habits, physical activity, adipokine profile, C-reactive protein (CRP), and circulating markers of endothelial dysfunction. A comparable cohort of NAFLD patients underwent a liver biopsy, an oral-glucose-tolerance test with minimal model analysis of glucose homeostasis variables, and an oral-fat-tolerance test with measurement of plasma lipoproteins, adipokines, and cytokeratin-18 fragments. RESULTS: SREBF-1c predicted the 7-y incidence of NAFLD (OR: 1.71; 95% CI: 1.15, 2.53) and diabetes and the 7-y elevation in CRP and endothelial dysfunction markers. In biopsy-proven NAFLD patients, the SREBF-1c A allele conferred increased risk of severe steatosis and nonalcoholic steatohepatitis; more-severe hepatic, muscle, and adipose tissue insulin resistance; and pancreatic ß cell dysfunction. SREBF-1c A allele carriers also had an impaired oral fat tolerance with a postprandial accumulation of large triglyceride-rich lipoproteins and oxidized LDLs, lower HDL cholesterol and adiponectin concentrations, and cytokeratin-18 fragment elevation. CONCLUSION: SREBF-1c polymorphism is associated with increased risk of developing NAFLD with more severe liver histology and derangement in glucose and lipoprotein metabolism, which contribute to the presentation and natural history of NAFLD.

Interactions among bone, liver, and adipose tissue predisposing to diabesity and fatty liver.

Growing epidemiological evidence connects obesity and its complications, including metabolic syndrome, diabetes, and nonalcoholic fatty liver disease (NAFLD) to reduced bone health and osteoporosis. Parallel to human studies, experimental data disclosed a complex network of interaction among adipose tissue, the liver, and the bone, which reciprocally modulate the function of each other. The main mediators of such crosstalk include hormonal/cytokine signals from the bone (osteopontin, osteocalcin, and osteoprotegerin), the liver (fetuin-A), and adipose tissue [leptin, tumor necrosis factor-α (TNF-α), and adiponectin]. Dysregulation of this network promotes the development of diabesity, NAFLD, and osteoporosis. We will review recent advances in understanding the mechanisms of bone-liver-adipose tissue interaction predisposing to obesity, diabetes, NAFLD, and osteoporosis and their potential clinical implications.

Sterol regulatory element-binding factor 2 (SREBF-2) predicts 7-year NAFLD incidence and severity of liver disease and lipoprotein and glucose dysmetabolism.

We prospectively assessed the impact of a sterol regulatory element-binding factor-2 (SREBF-2) polymorphism on the risk of developing nonalcoholic fatty liver disease (NAFLD) and on liver histology and lipoprotein and glucose metabolism in biopsy-proven NAFLD. In a population-based study, we followed 175 nonobese, nondiabetic participants without NAFLD or metabolic syndrome at baseline, characterized for the SREBF-2 rs133291 C/T polymorphism, dietary habits, physical activity, adipokines, C-reactive protein (CRP), and endothelial adhesion molecules. A comparable cohort of NAFLD patients underwent liver biopsy, an oral glucose tolerance test with minimal model analysis to yield glucose homeostasis parameters, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, and cytokeratin-18 fragments. After 7 years, 27% of subjects developed NAFLD and 5% developed diabetes. SREBF-2 predicted incident NAFLD and diabetes and CRP and endothelial adhesion molecule changes. In biopsy-proven NAFLD patients, SREBF-2 predicted nonalcoholic steatohepatitis (odds ratio 2.92 [95% CI 2.08-4.18], P = 0.002) and the severity of tissue insulin resistance, ß-cell dysfunction, and oral fat intolerance (characterized by higher postprandial lipemia, cholesterol enrichment of triglyceride-rich lipoproteins and oxidized LDLs, HDL cholesterol fall, adipokine imbalance, and postprandial apoptosis activation). An SREBF-2 polymorphism predisposes individuals to NAFLD and associated cardiometabolic abnormalities and affects liver histology and glucose and lipid metabolism in biopsy-proven NAFLD.

Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis.

Emerging experimental and human evidence has linked altered hepatic cholesterol homeostasis and free cholesterol (FC) accumulation to the pathogenesis of non-alcoholic steatohepatits (NASH). This review focuses on cellular mechanisms of cholesterol toxicity involved in liver injury and on alterations in cholesterol homeostasis promoting hepatic cholesterol overload in NASH. FC accumulation injures hepatocytes directly, by disrupting mitochondrial and endoplasmic reticulum (ER) membrane integrity, triggering mitochondrial oxidative injury and ER stress, and by promoting generation of toxic oxysterols, and indirectly, by inducing adipose tissue dysfunction. Accumulation of oxidized LDL particles may also activate Kupffer and hepatic stellate cells, promoting liver inflammation and fibrogenesis. Hepatic cholesterol accumulation is driven by a deeply deranged cellular cholesterol homeostasis, characterized by elevated cholesterol synthesis and uptake from circulating lipoproteins and by a reduced cholesterol excretion. Extensive dysregulation of cellular cholesterol homeostasis by nuclear transcription factors sterol regulatory binding protein (SREBP)-2, liver X-receptor (LXR)-α and farnesoid X receptor (FXR) plays a key role in hepatic cholesterol accumulation in NASH. The therapeutic implications and opportunities for normalizing cellular cholesterol homeostasis in these patients are also discussed.

Nonalcoholic steatohepatitis versus steatosis: adipose tissue insulin resistance and dysfunctional response to fat ingestion predict liver injury and altered glucose and lipoprotein metabolism.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis (SS) to nonalcoholic steatohepatitis (NASH). Though liver-related risk seems confined to NASH, it is currently unclear whether NASH has a higher risk of cardiovascular disease (CVD) and diabetes than SS as a result of the coexistence of obesity and other cardiometabolic confounders. Adipose tissue is an emerging modulator of liver disease in NAFLD and of cardiometabolic disease in the general population. We evaluated in SS and NASH (1) glucose homeostasis and cardiovascular risk profile and (2) the effect of adipose tissue dysfunction, assessed in fasting conditions and postprandially, on liver injury, glucose and lipoprotein metabolism, and markers of early atherosclerosis. Forty nonobese, nondiabetic, normolipidemic biopsy-proven NAFLD patients (20 with SS and 20 with NASH) and 40 healthy subjects, matched for overall/abdominal adiposity and metabolic syndrome, underwent an oral fat load test, with measurement of plasma triglyceride-rich lipoproteins, oxidized low-density lipoproteins, adipokines, and cytokeratin-18 fragments, and an oral glucose tolerance test with minimal model analysis to yield glucose homeostasis parameters. Circulating endothelial adhesion molecules were measured, and adipose tissue insulin resistance (adipose IR) index and visceral adiposity index were calculated. Despite similar fasting values, compared to SS, NASH showed a more atherogenic postprandial lipoprotein profile, an altered adipokine response (i.e., higher resistin increase and an adiponectin fall), and hepatocyte apoptosis activation after fat ingestion. Adipose IR index, endothelial adhesion molecules, and hepatic insulin resistance progressively increased across NAFLD stages. NASH, but not SS, showed an impaired pancreatic ß-cell function. On multiple regression analysis, adipose IR index and postprandial adiponectin independently predicted liver histology and altered cardiometabolic parameters. CONCLUSION: Adipose tissue dysfunction, including a maladaptive adipokine response to fat ingestion, modulates liver injury and cardiometabolic risk in NAFLD.

Obstructive sleep apnea-hypopnea syndrome and nonalcoholic fatty liver disease: emerging evidence and mechanisms.

Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are common conditions, frequently encountered in patients with metabolic disorders. OSAS has been associated with an increased risk of cardiovascular and metabolic complications. It has been recently suggested that the chronic intermittent hypoxia of OSAS may also affect the presence and severity of NAFLD. We will critically review experimental and human evidence connecting OSAS to NAFLD pathogenesis, trying to dissect the effect of intermittent hypoxia from that of obesity and associated comorbidities, and examine molecular mechanisms connecting OSAS to liver and metabolic disease in NAFLD, including hypoxia inducible factor (HIF), nuclear factor-kappa B, unfolded protein response, hypoxic adipose tissue inflammation, and their therapeutic potential for NAFLD and its complications, including cirrhosis and hepatocellular carcinoma. Finally, we will provide suggestions for the management of NAFLD patients with suspected OSAS and recommendations for future research.

Cholesterol-lowering therapy for the treatment of nonalcoholic fatty liver disease: an update.

PURPOSE OF REVIEW: To review recent human trials assessing cholesterol-lowering agents in nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS: Four randomized controlled trials (RCTs) assessed statins in NAFLD. In the only RCT with post-treatment biopsy, simvastatin did not change liver histology. In the remaining RCTs, atorvastatin was well tolerated, significantly improved radiological/biochemical markers of steatosis and plasma lipids, with neutral effects on glucose metabolism; in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study, atorvastatin reduced incident cardiovascular disease compared with both untreated NAFLD patients and with statin-treated patients without NAFLD. Ezetimibe was evaluated in two uncontrolled trials and two RCTs, consistently improving liver histology and plasma lipids, whereas glucose metabolism was generally unaffected; however, HbA1c increased with ezetimibe in one RCT. SUMMARY: From the analysis of available trials, it emerges that cholesterol-lowering agents may considerably benefit NAFLD patients. Statins are well tolerated, and atorvastatin improved surrogate markers of liver disease, whereas their effect on liver histology is unknown. Furthermore, the GREACE study was the first trial to show clinical benefit from the use of a pharmacological agent in NAFLD. Ezetimibe improved liver histology. The benefit of combination therapy, as well as the safety on glucose metabolism, need further evaluation.

Effect of lectin-like oxidized LDL receptor-1 polymorphism on liver disease, glucose homeostasis, and postprandial lipoprotein metabolism in nonalcoholic steatohepatitis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) affects 3-5% of the general adult population and predisposes to cirrhosis, cardiovascular disease (CVD), and diabetes through unclear mechanisms. Lectin-like oxidized LDL receptor-1 (LOX-1) has been connected to CVD risk in the general population and to insulin resistance and hepatic fibrogenesis in experimental models. OBJECTIVE: The objective was to assess the effect of the common functional LOX-1 IVS4-14 A→G polymorphism on liver disease, adipokines, oxidative stress, lipoprotein metabolism, and glucose homeostasis in NASH. DESIGN: Forty nonobese, nondiabetic, normolipidemic biopsy-proven NASH patients and 40 age-, sex-, BMI-, and LOX-1 IVS4-14 A→G polymorphism--matched healthy control subjects underwent an oral-fat-load test (OFT), with measurement of plasma triglyceride-rich lipoprotein (TRLP) subfractions, oxidized LDL, total antioxidant status (TAS), adipokines (resistin and adiponectin), and cytokeratin-18 fragments (marker of hepatocyte apoptosis). The subjects also underwent an oral-glucose-tolerance test (OGTT), with minimal model analysis to yield variables of glucose homeostasis. RESULTS: The LOX-1 polymorphism was independently associated with liver histology (G allele carriers had more severe liver disease); during the OFT, the G allele was associated with small TRLP accumulation, lower TAS, adipokine imbalance (higher resistin and lower adiponectin), and increased cytokeratin-18 fragments. The G allele was also independently associated with insulin resistance, impaired pancreatic ß cell function, and incretin effect during the OGTT. CONCLUSION: In NASH, the LOX-1 polymorphism is associated with liver disease severity and may predispose to CVD through modulation of postprandial small TRLPs and adipokine balance and to diabetes by affecting both insulin secretion and insulin sensitivity.

Loxin polymorphism is associated with increased resistin levels and with oxidative status.

OBJECTIVES: We hypothesized that LOX-1 polymorphism may impact on inflammation and cardiovascular risk by modulating systemic resistin expression. DESIGN AND METHODS: 276 men were randomly selected from a population-based cohort. Metabolic and inflammatory markers were evaluated at baseline and after 6-years follow-up, OLR1 (loxin) IVS4-14 A>G polymorphism was assessed. RESULTS: Mean plasma resistin and nitrotyrosine values were significantly higher, and TAS was significantly lowered in homozygous for the G allele. The G allele was significantly and directly associated with resistin and nitrotyrosine values. CONCLUSION: Enhanced oxidized-LDL uptake by LOX-1 G-allele carriers is associated with increased pro-oxidant status and resistin levels, suggesting a major uptake of ox-LDL by macrophages, smooth muscle cells, and monocytes.