Non-alcoholic Hepatosteatosis Research Articles

Prognostic Value of Non-HDL Cholesterol in COVID-19 Pneumonia.

In addition to coronary artery disease, non-high-density lipoprotein(non-HDL-C) provides short and long-term predictive information for many chronic inflammatory diseases such as stroke, hemodialysis, post-renal transplant, non-alcoholic hepatosteatosis, and human immunodeficiency virus. This study examined the predictive value of non-HDL-C measured before SARS-CoV-2 for mortality in COVID-19 infection. This study retrospectively included 1435 patients diagnosed with COVID-19 and treated in the thoracic diseases ward in a single center between January 2020 and June 2022. All patients included in the study had clinical and radiological features and signs of COVID-19 pneumonia. The COVID-19 diagnosis of all patients was confirmed by a polymerase chain reaction studied from an oropharyngeal swab. Statistical significance was set at p < 0.05. The study patients, including 1435 subjects, were divided into 712 patients in the non-surviving group and 723 in the surviving group. While there was no difference between the groups regarding gender, there was a statistically significant age difference. The non-surviving group was older. Age, lactate dehydrogenase(LDH), C reactive protein(CRP), triglycerides, D-dimer, and non-HDL-C were independent risk factors for mortality in regression analyses. In correlation analysis, age, CRP, and LDH were positively correlated with non-HDL-C. In the ROC analysis, sensitivity for non-HDL-C was 61.6%, and specificity was 89.2%. We believe that the non-HDL-C level studied before COVID-19 infection can be used as a prognostic biomarker for the disease.

Is serum uric acid-to-HDL cholesterol ratio elevation associated with diabetic kidney injury?

ABSTRACT Objectives Diabetic kidney injury (DKI) is a serious microvascular complicationof type 2 diabetes mellitus (T2DM). Novel markers are being developedto make a timely diagnosis of this complication. Uric Acid to HDLratio (UHR) was reported to be associated with inflammatory andmetabolic diseases such as metabolic syndrome, type 2 diabetesmellitus, thyroiditis, and nonalcoholic hepatosteatosis, recently. Inthe present study, we aimed to show the diagnostic role of UHR indiabetic kidney injury (DKI), a condition characterized with chronicand low-grade inflammation. Methods We retrospectively analyzed data of 287 patients who already had T2D Min outpatient clinics of our institution. The study population was divided into two groups according to the presence of DKI. General characteristics and laboratory data, including UHR levels, of the diabetic subjects with DKI were compared to those of patients without DKI. Results The median UHR of the diabetic patients with DKI group (0,13 (0,06-0,33)) was significantly elevated compared to the UHR of diabetic patients without DKI (0,11 (0,04-0,34)) (p < 0.001). Median UHR was significantly and positively correlated with UACR (r=0.14, p=0.02), serum creatinine (r=0.18, p=0.002), and HbA1c (r=0.28, p<0.001) levels. There was also a significant inverse correlation between UHR and GFR (r=-0.19, p=0.001) values. Logistic regression analysis confirmed that a 0.1 point increase in UHR increases DKI odds by 2.3 times. UHR was also correlated with serum creatinine, GFR, and UACR, which are important signs for DKI. Conclusion In conclusion, we think that UHR could be a diagnostic tool indiabetic kidney injury according to the preliminary results of the present study. UHR has an independent predictive role in DKI, and ithas significant correlation with other markers of kidney functions, therefore, we suggest routine evaluation of UHR in patients with DKIalong with other markers such as serum creatinine, GFR, and UACR.

Hepatocellular BChE as a therapeutic target to ameliorate hypercholesterolemia through PRMT5 selective degradation to restore LDL receptor transcription

AimsIndividuals with nonalcoholic hepatosteatosis (NAFLD) have a worse atherogenic lipoprotein profile and are susceptible to cardiovascular diseases. The MEK-ERK signaling cascades are central regulators of the levels of LDL receptor (LDLR), a major determinant of circulating cholesterol. It is elusive how hepatic steatosis contributes to dyslipidemia, especially hypercholesterolemia. Main methodsThe effects of BChE on signaling pathways were determined by immunoblotting in a BChE knockout hepatocyte cell line. DiI-LDL probe was used to explore the effect of BChE expression on LDL internalization. Co-immunoprecipitation and LC-MS were used to explore the interacting proteins with BChE. Finally, a hepatocyte-restricted BChE silencing mouse model was established by AAV8-Tbg-shRNA, and the hypercholesterolemia was induced by 65% kcal% high-fat, high-sucrose diet feeding. Main findingsHere we demonstrate that butyrylcholinesterase (BChE) governs the LDL receptor levels and LDL uptake capacity through the MEK-ERK signaling cascades to promote Ldlr transcription. BChE interacts and co-localizes with PRMT5, a protein methylation modifier controlling the ERK signaling. PRMT5 regulates LDLR-dependent LDL uptake and is a substrate of chaperone-mediated autophagy (CMA). BChE deficiency induces the PRTM5 degradation dependent on CMA activity, possibly through facilitating the HSC70 (Heat shock cognate 71 kDa) recognition of PRMT5. Remarkably, in vivo hepatocyte-restricted BChE silencing reduces plasma cholesterol levels substantially. In contrast, the BChE knockout mice are predisposed to hypercholesterolemia. SignificanceTaken together, these findings outline a regulatory role for the BChE-PRMT5-ERK-LDLR axis in hepatocyte cholesterol metabolism, and suggest that targeting liver BChE is an effective therapeutic strategy to treat hypercholesterolemia.

Влияние содержания витаминов D и B12 на частоту стеатогепатоза у детей с избыточной массой тела и ожирением

Актуальность. Неалкогольный стеатогепатоз у детей приводит к росту заболеваемости и смертности во взрослом возрасте. В последние годы опубликованы противоречивые данные о взаимосвязи между уровнями витаминов D и B12 и частотой неалкогольного стеатогепатоза. Цель исследования: оценить взаимосвязь между уровнем витаминов D и B12 и инсулинорезистентностью (ИР) и частотой неалкогольного стеатогепатоза у детей с ожирением и избыточной массой тела. Материалы и методы. В проспективное исследование были включены 167 детей с избыточной массой тела и ожирением в возрасте от 5 до 18 лет. Определяли антропометрические показатели, включая массу тела, рост, индекс массы тела (ИМТ) (вес/рост2, кг/м2). У детей и подростков с ИМТ ≥ 95-го перцентиля для возраста и пола диагностировали ожирение, а ИМТ от 85-го до 94-го перцентиля классифицировали как избыточную массу тела. Дети и подростки были разделены на две группы: со стеатогепатозом и без нарушения функционального состояния печени. Дополнительно оценивали состояние печени с помощью ультразвукового исследования. Определяли демографические характеристики участников исследования, проводили общеклинический обзор, лабораторные исследования, включая анализы на выявление уровня витамина В12 и 25(OH)D в сыворотке крови и определение индекса ИР. Результаты. Из 167 обследованных 103 (61,7 %) были мужского пола, 64 (38,3 %) — женского, их средний возраст составил 11,48 ± 2,99 года. Согласно ИМТ в 26,3 % случаев была выявлена избыточная масса тела, а в 73,7 % — ожирение. Стеатогепатоз диагностирован в 70,7 % случаев (n = 118), его частота была достоверно выше у пациентов мужского пола (79,6 %), чем женского (p = 0,001). Средний показатель ИР был статистически выше в группе детей со стеатогепатозом (11,15 ± 13,39), чем в контрольной группе (6,95 ± 6,20) (р = 0,029). Кроме того, установлены статистически значимые различия уровней ИР по степени выраженности стеатогепатоза (р = 0,013). Не наблюдалось достоверной взаимосвязи между дефицитом витаминов D и B12, наличием и тяжестью стеатогепатоза (p &gt; 0,05). Также не было выявлено статистически значимых различий между средним содержанием витаминов D и В12 и индексом ИР среди детей с ожирением и избыточной массой тела. Выводы. Полученные результаты подтверждают опубликованные ранее данные о том, что дефицит витаминов D и B12 не способствует развитию стеатогепатоза у детей с избыточной массой тела и ожирением. Инсулинорезистентность является фактором риска возникновения и прогрессирования стеатогепатоза.

Could triglyceride to high density lipoprotein-cholesterol ratio predict hepatosteatosis

Aim: The triglyceride / HDL cholesterol (TG/HDL-c) ratio is increased in a variety of diseases including, coronary heart disease and type 2 diabetes mellitus. However, its role in non-alcoholic hepatosteatosis is not well understood. In present study, we aimed to compare the TG/HDL-c levels of the patients with non-alcoholic hepatosteatosis to those of the healthy subjects. Methods: Medical data of the patients with non-alcoholic hepatosteatosis whom presented to the outpatient internal medicine clinics of our institution were retrospectively analyzed. Healthy subjects whom admissions to our clinics were due to check up were enrolled to the study as control group. TG/HDL-c of the groups compared. Results: TG/HDL-c level of the liver steatosis group (5 (2-22) %) was higher than the control group (2.7 (1-8) %), (p<0.001). TG/HDL-c was significantly and positively correlated with fasting blood glucose (r=0.31, p<0.001), C - reactive protein (r=0.25, p<0.001) and LDL-cholesterol (r=0.3, p<0.001) levels. A TG/HDL-c value greater than 3.1% has 91% sensitivity and 77% specificity in detecting hepatosteatosis. Conclusions: We suggest that TG/HDL-c ratio could be a useful marker of non-alcoholic hepatosteatosis due to its inexpensive and easy to assess nature.

The association of laminin levels with insulin resistance and non-alcoholic hepatosteatosis

BackgroundLaminin, one of the largest glycoproteins of the basement membrane, is an important component of the extracellular matrix. Functions of the basement membrane include regulation of cell signaling behaviors and structural support. Laminin plays a critical role in the regulation of insulin action in muscle, liver, and adipose tissue. The study mainly investigates an association between the change in serum laminin levels and insulin resistance and non-alcoholic hepatosteatosis.MethodsThis prospective study included a total of 90 participants; 60 patients diagnosed with Grade 2–3 non-alcoholic hepatosteatosis and 30 age- and sex-matched healthy controls between December 2019 and December 2020. Routine laboratory tests including glucose, insulin, homeostatic model of assessment-insulin resistance (HOMA-IR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and C-reactive protein and laminin levels were measured in the serum of the patient and control groups. Enzyme-linked immunosorbent assay was used for the measurement of laminin levels.ResultsThe median serum laminin levels were lower in patients with hepatic steatosis, compared to the control group (72 ng/L vs. 82 ng/L, respectively; p = 0.003). In the patients with insulin resistance, median laminin levels were lower, regardless of the presence of non-alcoholic hepatosteatosis (67 ng/L vs. 85 ng/L, respectively; p = 0.007). There was a weak, negative correlation between the laminin levels and HOMA-IR.ConclusionsOur study results suggest that, although there is no exact link between laminin and non-alcoholic hepatosteatosis, serum laminin levels are lower in patients with insulin resistance by regulating the insulin effect through integrins.

Predictors of 30-day readmission rate after total gastrectomy in patients with gastric malignancy.

e16109 Background: Total gastrectomy with lymph node dissection is curative for early gastric malignancy which accounts for 1.5% of cancer cases in the U.S. Readmissions are common postoperatively, and are associated with increased morbidity, mortality, hospital costs and decreased quality of life. We hence aim to identify incidence, impact and independent predictors for readmission in patients who underwent total gastrectomy in gastric malignancy. Methods: We conducted a retrospective cohort study of the 2017 National Readmission Database (NRD) of adult patients readmitted within 30 days after an index admission for total gastrectomy with a concomitant diagnosis of gastric malignancy. T-test was used for continuous variables and chi square test was used for categorical variables. Multivariate regression was used to identify predictors for unplanned readmissions. ICD 10 codes were used to identify diagnoses and procedures. Results: A total of 1,779 patients with gastric malignancy underwent total gastrectomy. The 30-day readmission rate was 18.5%. Main causes for readmission were sepsis, ventricular fibrillation, recurrent STEMI. Readmitted patients were more likely to be on chemotherapy. (40.1% vs 27.2%; P&lt;0.01) and more likely to be discharged to a skilled facility (13.5% vs 17.9%; P&lt;0.01). The total health care in-hospital economic burden of readmission was $6.5 million in total charges and $25 million in total costs. Independent predictors of readmission were major bleeding, respiratory failure requiring mechanical ventilation, peripheral parenteral nutrition, history of non-alcoholic hepato-steatosis, and prolonged length of stay. Conclusions: Readmissions after gastrectomy in patients with gastric malignancies are associated with lower in-hospital mortality yet pose a substantial economic burden on healthcare. The lower mortality might be explained by the relatively stable course and lower comorbidities of patients who become eligible for discharge after surgery. Further studies are suggested. Modifiable risk factors like malnutrition and sepsis warrant special attention to decrease readmissions and improve overall outcomes.[Table: see text]

TMEM41B acts as an ER scramblase required for lipoprotein biogenesis and lipid homeostasis

How amphipathic phospholipids are shuttled between the membrane bilayer remains an essential but elusive process, particularly at the endoplasmic reticulum (ER). One prominent phospholipid shuttling process concerns the biogenesis of APOB-containing lipoproteins within the ER lumen, which may require bulk trans-bilayer movement of phospholipids from the cytoplasmic leaflet of the ER bilayer. Here, we show that TMEM41B, present in the lipoprotein export machinery, encodes a previously conceptualized ER lipid scramblase mediating trans-bilayer shuttling of bulk phospholipids. Loss of hepatic TMEM41B eliminates plasma lipids, due to complete absence of mature lipoproteins within the ER, but paradoxically also activates lipid production. Mechanistically, scramblase deficiency triggers unique ER morphological changes and unsuppressed activation of SREBPs, which potently promotes lipid synthesis despite stalled secretion. Together, this response induces full-blown nonalcoholic hepatosteatosis in the TMEM41B-deficient mice within weeks. Collectively, our data uncovered a fundamental mechanism safe-guarding ER function and integrity, dysfunction of which disrupts lipid homeostasis.

Drak2 Aggravates Nonalcoholic Fatty Liver Disease Progression Through SRSF6-Associated RNA Alternative Splicing

Nonalcoholic hepatosteatosis (NASH) is an advanced stage of nonalcoholic fatty liver disease (NAFLD) with serious consequences that currently lacks approved pharmacological therapies. Recent studies suggest the close relationship between the pathogenesis of NAFLD and the dysregulation of RNA splicing machinery. Here, we revealed death-associated protein kinase-related apoptosis-inducing kinase-2(Drak2) is markedly upregulated in the livers of both patients and NAFLD/NASH diets-fed mice. Hepatic deletion of Drak2 suppresses the progression of hepatic steatosis to NASH. Comprehensive analyses of the phosphoproteome and transcriptome, indicated a crucial role of Drak2 in RNA splicing, and identified the splicing factor SRSF6 as a direct binding protein of Drak2. Further studies demonstrated that the binding of Drak2 inhibits phosphorylation of SRSF6 by the SRSF kinase(SRPK1) and regulates alternative splicing of mitochondrial function-related genes. In conclusion, our findings reveal an indispensable role of Drak2 in NAFLD/NASH and offer a potential therapeutic target for this disease.

Can portal vein pulsatility index be used as predictive parameter with hepatic artery resistive index for liver fibrosis in nonalcoholic hepatosteatosis?

Aim: Nonalcoholic fatty liver disease (NAFLD) is a clinical entity with a broad spectrum of isolated liver steatosis, steatohepatitis and even cirrhosis. In the development of hepatitis or cirrhosis, flow changes in the hepatic artery and portal vein may be detected. The aim of this study was to investigate the significance of the changes in hemodynamic findings according to the steatosis grade in patients with nonalcoholic hepatosteatosis. Materials and Methods: the study was performed with B-mode and Doppler ultrasonographic (US) measurements of patients who applied to the radiology department for abdominal ultrasonography examination between February and September 2018. Hepatic artery resistive index (HARI) and portal vein pulsatility index (PVPI) were evaluated. Thirty patients without steatosis and 30 patients from each 3 hepatosteatosis grade were included into the study. As the criteria for inclusion of patients in the study, there was no history of additional disease. p&amp;lt;0.05 values were considered statistically significant. Results: HARI was significantly lower in grade 3 steatosis than the control group, grade 1 and 2 steatosis (p&amp;lt;0.05). In grade 3 steatosis, portale vein diameter was significantly wider than the control group, grade 1 and 2 steatosis (p&amp;lt;0.05). PVPI was significantly lower in grade 2 steatosis than the control group and grade 1 steatosis (p&amp;lt;0.05). Significant hemodynamic changes were detected in the hepatic artery and portal vein when compared with control and patients groups. Conclusion: The evaluation of PVPI is considered as a noninvasive valuable method as if HARI in the evaluation of liver parenchymal damage in NAFLD.

Nonalcoholic Fatty Liver Disease and Diabetes: An Epidemiological Perspective.

Nonalcoholic fatty liver disease (NAFLD) is thought to stem from the body's inability to store excess energy in adipocytes; as such, it is commonly viewed as the hepatic manifestation of metabolic syndrome. The pathogenesis of NAFLD involves ectopic fat accumulation, which also takes place in the liver, muscle and visceral fat. NAFLD is rapidly becoming more widespread in Korea, with an estimated prevalence of 30% in adults. Type 2 diabetes mellitus (T2DM) and NAFLD share insulin resistance as a common pathophysiological mechanism, and each of these two diseases affects the development of the other. Recent studies have suggested that NAFLD is often present as a comorbidity in T2DM patients. The mutual interrelationship between these conditions is shown by findings suggesting that T2DM can exacerbate NAFLD by promoting progression to nonalcoholic hepatosteatosis or fibrosis, while NAFLD causes the natural course of diabetic complications to worsen in T2DM patients. It remains unknown whether one disease is the cause of the other or vice versa. In this review, I would like to discuss current epidemiological data on the associations between NAFLD and T2DM, and how each disease affects the course of the other.

Loss of RIP3 initiates annihilation of high-fat diet initialized nonalcoholic hepatosteatosis: A mechanism involving Toll-like receptor 4 and oxidative stress

Non-alcoholic fatty liver disease (NAFLD) is a prevalent and complex disease that confers a high risk of severe liver disorders. Although such public and clinical health importance, very few effective therapies are presently available for NAFLD. Here, we showed that receptor-interacting kinase-3 (RIP3) was up-regulated in liver of mouse with hepatic steatosis induced by high fat diet (HFD). After 16 weeks on a HFD, obesity, insulin resistance, metabolic syndrome, hepatic steatosis, inflammatory response and oxidative stress were significantly alleviated in liver of mice with the loss of RIP3. We provided mechanistic evidence that RIP3 knockdown attenuated hepatic dyslipidemia through preventing the expression of lipogenesis-associated genes. Furthermore, in the absence of RIP3, the transcription factor of nuclear factor-κB (NF-κB) signaling pathway activated by HFD was blocked, accompanied with the inhibition of NLRP3 inflammasome. We also found that RIP3 knockdown-induced activation of nuclear factor-erythroid 2 related factor 2/heme oxygenase-1 (Nrf-2/HO-1) led to the inhibition of oxidative stress. The detrimental effects of RIP3 on hepatic steatosis and related pathologies were confirmed in palmitate (PAL)-treated mouse liver cells. Of note, lipopolysaccharide (LPS)- or PAL-activated TLR-4 resulted in the up-regulation of RIP3 that was accompanied by the elevated inflammation and lipid deposition, and these effects were reversed in TLR-4 knockdown cells. Furthermore, promoting Nrf-2 pathway activation effectively reduced reactive oxygen species (ROS) generation and RIP3 expression in PAL-stimulated cells, consequently leading to the suppression of cellular inflammation and lipid accumulation. In contrast, blocking Nrf-2/HO-1 signaling abrogated RIP3 knockdown-reduced reactive oxygen species (ROS), inflammatory response and lipid deposition in PAL-stimulated cells. Taken together, the present study helped to elucidate how HFD-induced hepatic steatosis was regulated by RIP3, via the TLR-4/NF-κB and Nrf-2/HO-1 signaling pathways.

Vitamin E - The Next 100 Years.

α-Tocopherol is the only tocopherol that has been shown to prevent the human deficiency disease Ataxia with Isolated Vitamin E Deficiency (AVED), and thus it is the only one that, for humans, can be called vitamin E. Vitamin E in addition to preventing AVED has documented immune boosting properties and an activity against nonalcoholic hepatosteatosis and low-grade inflammation. Epidemiological studies indicating that vitamin E could prevent cardiovascular events, neurodegenerative disease, macular degeneration, and cancer were in general not confirmed by clinical intervention studies. Vitamin E and some of its metabolites modulate cell signaling and gene transcription. Future research is needed to achieve a better understanding of the molecular events leading to gene regulation by vitamin E, especially in its phosphorylated form. Isolation and characterization of the vitamin E kinase and vitamin E phosphate phosphatase will help in the understanding of cell regulation processes modulated by vitamin E. A clarification of the pathogenesis of AVED remains an important goal to be achieved. © 2018 IUBMB Life, 71(4):411-415, 2019.

Successful therapy of plaque-type psoriasis with secukinumab in patients with multiple comorbidities treated with previous biologic therapies

Purpose: Biologic therapy in psoriatic patients with multiple comorbidities is challenging due to worsening of associated diseases and possible side effects of concomitant medications.Materials and methods: We describe three patients with multiple comorbidities documenting successful treatment of psoriasis with secukinumab following failure of multiple conventional and biologic DMARDs.Results: The first case is an obese 59-year-old woman (HBV + with latent tuberculosis) with arterial hypertension and 12-year history of breast cancer. The second is a 45-year-old obese man (HCV + with occult HBV infection on therapy with multiple antipsychotics and taking methadone for opioid dependence), while the last is a 39-year-old man with severe obesity, non-alcoholic hepatosteatosis, and NYHA class II heart failure. All three patients had undergone previous conventional (methotrexate, cyclosporine, retinoids, and phototherapy) and multiple biologic treatments (one or more of the following: adalimumab, ustekinumab, etanercept, infliximab originator, and biosimilar) that were discontinued for inefficacy and/or adverse effects. All patients underwent therapy with secukinumab, which was associated with sustained clinical benefits and no clinically relevant safety findings.Conclusions: The present three cases add further evidence that secukinumab is effective and well tolerated in difficult to treat psoriatic patients with multiple comorbidities, namely HBV, latent TBC infection, and hepatic impairment.

A Controlled Fermented Samjunghwan Herbal Formula Ameliorates Non-alcoholic Hepatosteatosis in HepG2 Cells and OLETF Rats.

Hepatosteatosis (HS), a clinical feature of fatty liver with the excessive intracellular accumulation of triglyceride in hepatocytes, is manifested by perturbation of the maintenance of liver lipid homeostasis. Samjunghwan (SJH) is an herbal formula used mostly in Korean traditional medicine that is effective against a number of metabolic diseases, including obesity. Herbal drugs, enriched with numerous bioactive substances, possess health-protective benefits. Meanwhile, fermented herbal products enriched with probiotics are known to improve metabolic processes. Additionally, current lines of evidence indicate that probiotics-derived metabolites, termed as postbiotics, produce the same beneficial effects as their precursors. Herein, the anti-HS effects of 5-weeks naturally fermented SJH (FSJH) was investigated with FSJH-mixed chow diet in vivo using Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats as animal models of HS and controls, respectively. In parallel, the anti-HS effects of postbiotic-metabolites of three bacterial strains [Lactobacillus brevis (LBB), Lactococcus lactis (LCL) and Lactobacillus plantarum (LBP)] isolated from FSJH were also evaluated in vitro using the FFAs-induced HepG2 cells. Feeding OLETF rats with FSJH-diet effectively reduced body, liver, and visceral adipose tissue (VAT) weights, produced marked hypolipidemic effects on serum and hepatic lipid parameters, decreased serum AST and ALT levels, and upregulated the HMGCOR, SREBP, and ACC, and downregulated the AMPK and LDLR gene expressions levels. Additionally, exposure of FFAs-induced HepG2 cells to postbiotic metabolic media (PMM) of bacterial strains also produced marked hypolipidemic effects on intracellular lipid contents and significantly unregulated the HMGCOR, SREBP, and ACC, and downregulated the AMPK and LDLR genes expressions levels. Overall, our results indicate that FSJH enriched with fermented metabolites could be an effective anti-HS formulation.

Treating nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a review of efficacy and safety.

To review current literature for the efficacy and safety of treatment for nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). A PubMed literature search from January 1990 to June 2017 was conducted using the search terms nonalcoholic fatty liver disease, diabetes mellitus, type 2, therapy, treatment, treat, therapeutics, nonalcoholic fatty liver, nonalcoholic hepatosteatosis, NASH, NAFLD, metformin, and statin. Bibliographies of chosen articles were reviewed. Relevant articles on metformin, thiazolidinediones (TZD), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and statins for the treatment of NAFLD which included patients with T2DM were reviewed. A total of 23 relevant studies were found and included randomized controlled, observational, and open-label designs, as well as three meta-analyses. Metformin combined with weight loss provides a modest improvement in steatosis and no improvement in fibrosis in patients with NAFLD and T2DM. TZDs showed positive results on fibrosis and resolution of NASH but at least half of patients studied were nonresponders. GLP-1 RAs also showed favorable results on reductions in transaminases and steatosis and improvements in insulin sensitivity and weight loss but lack efficacy data for resolution of NASH or improvement in fibrosis scores. Statins showed favorable results on reductions in transaminases but mixed results for improvement in steatosis and fibrosis scores. All reviewed treatment options are safe for management of NAFLD in patients with T2DM but long-term histological improvements are minimal. TZDs are efficacious for resolution of NASH and improvements in fibrosis but long-term use is required to maintain these results.

Autophagy in the liver: cell’s cannibalism and beyond

Chronic liver disease and its progression to liver failure are induced by various etiologies including viral infection, alcoholic and nonalcoholic hepatosteatosis. It is anticipated that the prevalence of fatty liver disease will continue to rise due to the growing incidence of obesity and metabolic disorder. Evidence is accumulating to indicate that the onset of fatty liver disease is causatively linked to mitochondrial dysfunction and abnormal lipid accumulation. Current treatment options for this disease are limited. Autophagy is an integral catabolic pathway that maintains cellular homeostasis both selectively and nonselectively. As mitophagy and lipophagy selectively remove dysfunctional mitochondria and excess lipids, respectively, stimulation of autophagy could have therapeutic potential to ameliorate liver function in steatotic patients. This review highlights our up-to-date knowledge on mechanistic roles of autophagy in the pathogenesis of fatty liver disease and its vulnerability to surgical stress, with an emphasis on mitophagy and lipophagy.

Discovering a critical transition state from nonalcoholic hepatosteatosis to nonalcoholic steatohepatitis by lipidomics and dynamical network biomarkers.

Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for type 2 diabetes and metabolic syndrome. However, accurately differentiating nonalcoholic steatohepatitis (NASH) from hepatosteatosis remains a clinical challenge. We identified a critical transition stage (termed pre-NASH) during the progression from hepatosteatosis to NASH in a mouse model of high fat-induced NAFLD, using lipidomics and a mathematical model termed dynamic network biomarkers (DNB). Different from the conventional biomarker approach based on the abundance of molecular expressions, the DNB model exploits collective fluctuations and correlations of different metabolites at a network level. We found that the correlations between the blood and liver lipid species drastically decreased after the transition from steatosis to NASH, which may account for the current difficulty in differentiating NASH from steatosis based on blood lipids. Furthermore, most DNB members in the blood circulation, especially for triacylglycerol (TAG), are also identified in the liver during the disease progression, suggesting a potential clinical application of DNB to diagnose NASH based on blood lipids. We further identified metabolic pathways responsible for this transition. Our study suggests that the transition from steatosis to NASH is not smooth and the existence of pre-NASH may be partially responsible for the current clinical limitations to diagnose NASH. If validated in humans, our study will open a new avenue to reliably diagnose pre-NASH and achieve early intervention of NAFLD.

Activation of hepatic stellate cell in Pten null liver injury model.

BackgroundHepatic fibrosis is a prominent pathological feature associated with chronic liver disease including non-alcoholic hepatosteatosis (NASH), and a precursor for liver cancer development. We previously reported that PTEN loss in the liver, which leads to hyperactivated liver insulin signaling results in NASH development. Here we used the same mouse model to study the progression from steatosis to fibrosis.ResultsThe Pten null livers develop progressive liver fibrosis as indicated by Sirius Red staining and increased expression of collagen I, Timp 1, SMAα, and p75NTR. Consistently, hepatic stellate cells (HSCs) isolated from Pten null livers are readily activated when compared with that from mice with intact PTEN. Deletion of AKT2, the downstream target of PTEN signal, blocked NASH development, and alleviated fibrosis. HSCs from the Pten/Akt2 double null mice are quiescent like those isolated from the control livers. Our analysis shows that the activation of HSCs does not depend on the intrinsic signals regulated by PI3K/AKT, the target of PTEN, but does depend on steatosis and injury to the liver. During the progression of liver fibrosis in the Pten null model, Wnt ligands and signaling receptor are induced, concurrent with the reduction of sFRP5, a Wnt antagonist. We showed that treatment of HSCs with Wnt receptor antagonist blocks the observed morphological changes when HSCs undergo activation in culture. This signal appears to be mediated by β-catenin, as manipulating β-catenin signaling alters marker gene expressions of HSC activation.ConclusionsWnt/β-catenin activation serves as an important mediator for fibrosis development resulting from NASH using a mouse model where NASH is mimicked by PTEN loss.

Adipocytokines in obesity and metabolic disease

The current global obesity pandemic is the leading cause for the soaring rates of metabolic diseases, especially diabetes, cardiovascular disease, hypertension, and non-alcoholic hepatosteatosis. Efforts devoted to find cures for obesity and associated disorders in the past two decades have prompted intensive interest in adipocyte biology, and have led to major advances in the mechanistic understanding of adipose tissue as an essential endocrine organ. Adipose tissue secretes an array of hormones (adipokines) that signal key organs to maintain metabolic homeostasis, and their dysfunction has been causally linked to a wide range of metabolic diseases. In addition, obesity induces production of inflammatory cytokines (often referred to together with adipokines as adipocytokines) and infiltration of immune cells into adipose tissue, which creates a state of chronic low-grade inflammation. Metabolic inflammation has been increasingly recognized as a unifying mechanism linking obesity to a broad spectrum of pathological conditions. This review focuses on classic examples of adipocytokines that have helped to form the basis of the endocrine and inflammatory roles of adipose tissue, and it also details a few newly characterized adipocytokines that provide fresh insights into adipose biology. Studies of adipocytokines in clinical settings and their therapeutic potential are also discussed.