Nonalcoholic Fatty Liver Disease Remission Research Articles

Downregulation of Setdb2 promotes alternative activation of macrophages via the PI3K/Akt pathway to attenuate NAFLD after sleeve gastrectomy

Non-alcoholic fatty liver disease (NAFLD) stands as the most prevalent hepatic disorder, with bariatric surgery emerging as the most effective intervention for NAFLD remission. Sleeve gastrectomy (SG) has notably ascended as the predominant procedure due to its comparative simplicity and consistent surgical outcomes. Nonetheless, the underlying mechanisms remain unclear. In this study, we probed the therapeutic potential of SG for NAFLD induced by a high-fat diet (HFD) in mice, with a focus on its impact on liver lipid accumulation, macrophage polarization, and the role of the histone methyltransferase Setdb2. SG prompted significant weight loss, diminished liver size and liver-to-body weight ratio, and enhanced liver function, evidenced by reduced serum levels of triglycerides (TG), total cholesterol (T-CHO), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Histological examination confirmed a reduction in liver lipid accumulation. Additionally, flow cytometry unveiled an increased proportion of M2 macrophages and a decrease in Setdb2 expression was shown in the SG group, suggesting an association between Setdb2 levels and postsurgical macrophage polarization. Furthermore, the conditional knockout of Setdb2 in mice further mitigated HFD-induced steatosis and promoted the M2 macrophage phenotype. Mechanistically, Setdb2 knockout in bone marrow-derived macrophages (BMDMs) favored M2 polarization, with RNA sequencing and western blotting analyses corroborating the upregulation of the PI3K/Akt signaling pathway. The effects of Setdb2 on macrophage activation were nullified by the PI3K inhibitor LY294002, suggesting that Setdb2 facilitates alternative macrophage activation through the PI3K/Akt signaling pathway. These comprehensive findings underscore the potential of SG as a therapeutic intervention for NAFLD by regulating the critical function of Setdb2 in macrophage polarization and activation, thereby offering novel insights into NAFLD pathogenesis and therapeutic targets.

Data-Driven Patient clusters of Type 2 Diabetes May Help to Identify Patients at Risk and Predict Metabolic Surgery Outcomes on Diabetes Remission and NAFLD Pregression

Abstract Background Precision medicine and customized medicine have gained enormous attention in recent years, especially in the treatment of type 2 diabetes (T2D). Different subgroups of diabetes have been identified by research employing data-driven cluster analysis, each with a unique diabetes progression and complication risk (Ahlqvist et al., Lancet Diabetes Endocrinol. 2018). Aims We aimed to apply the proposed cluster analysis to a patent population post metabolic surgery and investigate the association with T2D remission and presence of NAFLD. Methods We retrospectively linked newly defined clusters to metabolic surgery outcomes in 53 T2D patients. Utilizing k-means and hierarchical clustering, three clusters emerged based on glutamate decarboxylase antibodies, age, BMI, HbA1c, and homoeostatic model assessment estimates of β-cell function (HOMA2-B%) and insulin resistance (HOMA2-IR). Intraoperative liver biopsies assessed nonalcoholic fatty liver disease (NAFLD) presence differentiating between simple steatosis (NAFL) and steatohepatitis (NASH). Clinical and biochemical data were collected over two years, focusing on T2D remission and NAFLD improvement. Results Cluster 1, characterized by the lowest BMI, highest NASH rate, impaired beta-cell function, and increased insulin resistance, displayed a favorable response to surgery, indicating robust regeneration of beta-cells. Despite increased insulin production, T2D remission was surprisingly low at 44.0% after one year, in contrast to 75.00% in Cluster 2 and 100.00% in Cluster 3. Metabolic surgery notably reduced insulin resistance and promoted NASH remission, evidenced by a significant reduction in a non-invasive NASH detection score and liver enzyme levels across all three clusters. Conclusion Our findings suggest that patients in Cluster 1 already show a lack of beta-cell compensation being associated with a higher prevalence of NAFLD and poorer diabetic control and therefore especially might benefit from an earlier intervention. Data-driven classification might help to customize treatment plans and identify patients at higher risk of problems at diagnosis.

Changes in nonalcoholic fatty liver disease and M2BPGi due to lifestyle intervention in primary healthcare.

A healthy lifestyle is the most important method for managing nonalcoholic fatty liver disease (NAFLD). Mac-2-binding protein glycosylated isomer (M2BPGi) has been suggested as a biomarker for NAFLD. This study aimed to determine the efficacy of personalized lifestyle interventions on NAFLD remission. This single-arm intervention study recruited participants with NAFLD who underwent health checkups at seven health-promotion centers in five South Korean cities. Fatty liver diagnosis was based on ultrasonography (US). The 109 individuals were recruited for personalized lifestyle interventions of hypocaloric diets and exercise. The participants attended the lifestyle intervention programs once per month for the first 3 months, and once every 3 months for the subsequent 6 months. In addition to sessions through center visits, phone-based intervention and self-monitoring at 4-, 5-, 7-, and 8-month were provided during the 9-month intervention period. And phone-based self-monitoring were also provided monthly during the 3-month follow-up period. The primary outcome was NAFLD remission at month 12 as measured on US and magnetic resonance elastography. The secondary outcomes were the changes in metabolic factors and M2BPGi. The 108 individuals (62 males and 46 females; age 51.1±12.4 years, mean±standard deviation) were finally analyzed after the 12month intervention. Body mass index, waist circumference (WC), blood pressure, blood lipids (total cholesterol, triglycerides, and HDL-C), and fasting blood sugar levels were improved relative to baseline (all P<0.05). Fatty liver at or above the moderate grade according to US was decreased at month 12 relative to baseline (67.6% vs 50.9%) (P = 0.002). M2BPGi levels decreased during the 12-month study period (P<0.001). M2BPGi levels were moderately correlated with hepatic fat fraction by magnetic resonance imaging (r = 0.33, P = 0.05). WC (OR = 0.82, 95% CI = 0.67-1.00, P = 0.05) and HDL-C (OR = 1.17, 95% CI = 1.03-1.32, P = 0.014) were associated with remission of fatty liver in the multivariate analysis. The personalized lifestyle intervention was effective in improving fatty liver and metabolic factors, but not hepatic stiffness, in NAFLD. ICTRP, cris.nih.go.kr (KCT0006380).

Remission of Nonalcoholic Fatty Liver Disease After Radical Surgery in Patients with Colorectal Cancer: A Single-Center Retrospective Study.

Purpose: The purpose of this study was to investigate the relationship between remission of nonalcoholic fatty liver disease (NAFLD) and radical surgery for colorectal cancer (CRC) patients. Methods: From January 2014 to December 2021, data of patients with concurrent CRC and NAFLD who underwent radical surgery in a single-center hospital were retrospectively collected. NAFLD was defined as a mean computed tomography (CT) liver attenuation value of <40 Hounsfield units (HUs). Comparison of preoperative and 1-year postoperative CT images was performed to evaluate the change of NAFLD. Multivariate logistic regression analysis was performed to identify independent predictive factors for NAFLD remission. The Kaplan-Meier method was used to estimate overall survival (OS) and disease-free survival (DFS) between the remission group and no remission group. Results: In this study, a total of 55 eligible patients were included. The remission group had 33 (60.0%) patients and the no remission group had 22 (40.0%) patients. The mean preoperative weight was 66.1 ± 9.9 kg. The mean preoperative body mass index (BMI) was 25.4 ± 2.5 kg/m2. We found that the average weight was significantly decreased (P < 0.01), average BMI was significantly decreased (P < 0.01), and HU score was significantly increased (P < 0.01). By comparing baseline characteristics between the remission group and no remission group, we found that the remission group exhibited larger tumor sizes (P = 0.036) than the no remission group. In the multivariate logistic regression analysis, we found that weight change was a predictor for NAFLD (odds ratio = 0.764, 95% confidence interval = 0.618-0.944, P = 0.013). We did not find any statistically significant differences in OS (P = 0.182) or DFS (P = 0.248) between the remission group and no remission group. Conclusions: The NAFLD remission rate reached 60.0% for CRC patients 1 year after radical surgery. In addition, we found that weight change was a predictor of NAFLD remission.

Changes in mesenteric fat thickness and its clinical impact in bariatric surgery.

Obesity, especially central obesity is associated with increased risk of metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus. The study aimed to investigate the associations of the changes of abdominal fat thicknesses with changes of anthropometric indexes and improvements of metabolic phenotypes in patients with obesity and T2DM before and after bariatric surgery. Between April 2016 and January 2017, 34 adult patients with concurrent obesity and T2DM scheduled for different bariatric surgeries were prospectively evaluated by ultrasound before and 1-year after bariatric surgery to determine abdominal fat thicknesses (mesenteric fat, preperitoneal fat and subcutaneous fat) and NAFLD. At 1 year, of the 25 patients that finished the study, significant decrease in mesenteric-fat-thickness was associated with significant reduction of obesity, that is, BMI (-24%, p < .001), remission of metabolic syndrome (32%, p = .008), NAFLD (60%, p < .001) and T2DM (44%, p < .001). Lower baseline mesenteric fat thickness was associated with remission of metabolic syndrome. Lower baseline mesenteric-fat-thickness may have the potential to predict metabolic syndrome remission after bariatric surgery.

Nonalcoholic Fatty Liver Disease Incidence and Remission and Their Predictors During 7 Years of Follow-up Among Finns.

The incidence and remission of nonalcoholic fatty liver disease (NAFLD) are sparsely studied outside Asia. This prospective study aimed to investigate NAFLD incidence and remission, and their predictors among a general Finnish population. The applied cohort included 1260 repeatedly studied middle-aged participants with data on liver ultrasound and no excessive alcohol intake. Hepatic steatosis was assessed by liver ultrasound with a 7.2-year study interval. Comprehensive data on health parameters and lifestyle factors were available. At baseline, 1079 participants did not have NAFLD, and during the study period 198 of them developed NAFLD. Of the 181 participants with NAFLD at baseline, 40 achieved NAFLD remission. Taking multicollinearity into account, key predictors for incident NAFLD were baseline age (odds ratio 1.07; 95% CI, 1.02-1.13; P = .009), waist circumference (WC) (2.77, 1.91-4.01 per 1 SD; P < .001), and triglycerides (2.31, 1.53-3.51 per 1 SD; P < .001) and alanine aminotransferase (ALAT) (1.90, 1.20-3.00 per 1 SD; P = .006) concentrations as well as body mass index (BMI) change (4.12, 3.02-5.63 per 1 SD; P < .001). Predictors of NAFLD remission were baseline aspartate aminotransferase (ASAT) concentration (0.23, 0.08-0.67 per 1 SD; P = .007) and WC change (0.38, 0.25-0.59 per 1 SD; P < .001). During follow-up, NAFLD developed for every fifth participant without NAFLD at baseline, and one-fifth of those with NAFLD at baseline had achieved NAFLD remission. NAFLD became more prevalent during the follow-up period. From a clinical perspective, key factors predicting NAFLD incidence and remission were BMI and WC change independent of their baseline level.

The change of non-alcoholic fatty liver disease is associated with risk of incident diabetes.

The effect of change in non-alcoholic fatty liver disease (NAFLD) status on incident diabetes has not been well studied. We aimed to investigate the association of NAFLD development and remission with the risk of incident diabetes during a median of 3.5-year follow-up. A total of 2690 participants without diabetes were recruited in 2011-2012 and assessed for incident diabetes in 2014. Abdominal ultrasonography was used to determine the change of NAFLD. 75g oral glucose tolerance test (OGTT) was performed to determine diabetes. NAFLD severity was assessed using Gholam's model. The odds ratios (ORs) for incident diabetes were estimated by logistic regression models. NAFLD was developed in 580 (33.2%) participants and NAFLD remission occurred in 150 (15.9%) participants during a median of 3.5-year follow-up. A total of 484 participants developed diabetes during follow-up, including 170 (14.6%) in consistent non-NAFLD group, 111 (19.1%) in NAFLD developed group, 19 (12.7%) in NAFLD remission group, and 184 (23.2%) in sustained NAFLD group. The development of NAFLD increased the risk of incident diabetes by 43% (OR, 1.43; 95%CI, 1.10-1.86) after adjustment for multiple confounders. Compared with sustained NAFLD group, remission of NAFLD reduced the risk of incident diabetes by 52% (OR, 0.48; 95%CI, 0.29-0.80). The effect of NAFLD alteration on incident diabetes was not changed after adjustment for body mass index or waist circumference, change of body mass index or waist circumference. In NAFLD remission group, participants with non-alcoholic steatohepatitis (NASH) at baseline were more likely to develop diabetes (OR, 3.03; 95%CI, 1.01-9.12). NAFLD development increases the risk of incident diabetes, whereas NAFLD remission reduces the risk of incident diabetes. Moreover, presence of NASH at baseline could attenuate the protective effect of NAFLD remission on incident diabetes. Our study suggests that early intervention of NAFLD and maintenance of non-NAFLD are important for prevention of diabetes.

A greater ratio of thigh subcutaneous fat to abdominal fat is associated with protection against non-alcoholic fatty liver disease

Background & AimsNo prospective studies have examined the association between thigh subcutaneous fat distribution and non-alcoholic fatty liver disease (NAFLD). We investigated the associations of thigh subcutaneous fat distribution with incidence and remission of NAFLD in a community-based prospective cohort. MethodsWe followed 1,787 subjects, who underwent abdominal ultrasonography, abdominal and femoral magnetic resonance imaging scans, and anthropometric assessments. Associations of thigh subcutaneous fat area/abdominal fat area ratio and thigh circumference/waist circumference ratio with incidence and remission of NAFLD were estimated using the modified Poisson regression model. ResultsOver a mean 3.6-year follow-up, 239 incident cases of NAFLD and 207 regressed cases of NAFLD were identified. Increasing thigh subcutaneous fat area/abdominal fat area ratio was associated with a lower risk of incident NAFLD and a higher likelihood of remission of NAFLD [risk ratio (RR) per SD: 0.69, 95% CI 0.59-0.81; 1.20, 95% CI 1.07-1.34, respectively). Each one SD increase in thigh circumference/waist circumference ratio was associated with a 16% lower risk of incident NAFLD (RR 0.84, 95% CI 0.76-0.94) and a 22% higher likelihood of remission of NAFLD (RR 1.22, 95% CI 1.11-1.34). Additionally, the effects of thigh subcutaneous fat area/abdominal fat area ratio on the incidence and remission of NAFLD were mediated through adiponectin (14.9% and 26.6%), homeostasis model assessment of insulin resistance (9.5% and 23.9%), and triglyceride (7.5% and 19.1%). ConclusionsThese results demonstrated that a favourable fat distribution, characterised by a greater ratio of thigh subcutaneous fat to abdominal fat, had a protective role against NAFLD. Impact and implicationsThe associations of thigh subcutaneous fat distribution with NAFLD incidence and remission have not been prospectively examined in a community-based cohort. Our findings suggest that greater thigh subcutaneous fat relative to a given amount of abdominal fat has a protective effect against NAFLD among the middle-aged and older Chinese populations.

Preoperative circulating peroxiredoxin 1 levels as a predictor of non-alcoholic fatty liver disease remission after laparoscopic bariatric surgery.

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and insulin resistance and can be improved after bariatric surgery. Circulating Peroxiredoxin 1 (Prdx1) protein was reported to regulate energy metabolism and inflammation. This study aimed to investigate the roles of serum prdx1 in NAFLD patients with obesity undergoing LSG and to develop a prognostic model to predict the remission of severe NAFLD. The data of 93 participants from a tertiary hospital were assessed. Before laparoscopic sleeve gastrectomy (LSG) and three months after LSG, anthropometric parameters, laboratory biochemical data, and abdominal B-ultrasound results were collected, and their hepatic steatosis index (HSI) and triglyceride-glucose index (TyG) were calculated. A NAFLD improvement (NAFLD-I) nomogram prediction model was constructed using the least absolute shrinkage and selection operator (LASSO) regression and multiple regression, and its predictive ability was verified in a validation cohort. The baseline Prdx1 (OR: 0.887, 95% CI: 0.816-0.963, p=0.004), preoperative TyG (OR: 8.207, 95% CI: 1.903-35.394, p=0.005) and HSI (OR: 0.861, 95% CI: 0.765-0.969, p=0.013) levels were independently associated with NAFLD-I at three months after LSG in NAFLD patients with obesity. In the primary and validation cohorts, the area under the receiver operating characteristic (AUC) of the developed nomogram model was 0.891 and 0.878, respectively. The preoperative circulating Prdx1 levels of NAFLD patients with obesity were significantly reduced after LSG (25.32 [18.99-30.88] vs. 23.34 [15.86-26.42], p=0.001). Prdx1 was related to obesity and hepatic steatosis based on correlation analysis. The nomogram based on preoperative serum prdx1, HSI and TyG could be an effective tool for predicting remission of severe NAFLD after LSG.

Combined non-alcoholic fatty liver disease and type 2 diabetes in severely obese patients-medium term effects of sleeve gastrectomy versus Roux-en-Y-gastric bypass on disease markers.

We aimed to evaluate the medium-term efficacy of sleeve gastrectomy (SG) vs. Roux-en-Y gastric bypass (RYGB) on remission of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). We identified severely obese patients [body mass index (BMI) >35 kg/m2] with NAFLD (as defined by the Longitudinal Assessment of Bariatric Surgery Study) and T2DM (as defined by the American Association of Clinical Endocrinologists and the American College of Endocrinology) who underwent SG or RYGB in a single university surgical centre. The cohorts were match-paired and data were analysed after at least 3 years of follow up. The key outcomes measured were: (I) the improvement of liver function tests and NAFLD markers; (II) glycemic control and insulin resistance. Ninety-six patients were investigated; 44 (45.8%) were women. The mean pre-operative BMI was 45.2 kg/m2 in the SG and 42.0 kg/m2 in the RYGB group. SG and RYGB both significantly reduced serum liver enzyme concentrations. NAFLD markers resolved 2 years after SG in all patients. In contrast, only 78% and 80% of patients achieved remission of NAFLD 2 and 3 years after RYBG respectively. Both procedures resulted in comparable rates of remission of T2DM. Bariatric surgery with SG may be preferable to RYGB for obese patients with NAFLD and T2DM based on the rates of remission of markers of these co-morbidities. However, our results need to be confirmed in prospective trials. Understanding the metabolic effects of specific bariatric surgical procedures may facilitate the development of a personalised approach to weight-loss surgery.

High Meat Consumption Is Prospectively Associated with the Risk of Non-Alcoholic Fatty Liver Disease and Presumed Significant Fibrosis.

Non-alcoholic fatty liver disease (NAFLD) has been associated with meat consumption in cross-sectional studies. However, only a few prospective studies have been conducted, and they did not test for liver fibrosis. We aimed to assess the association between meat consumption changes and the incidence and remission of NAFLD and significant liver fibrosis. We used a prospective cohort study design, including 316 subjects aged 40–70 years, participating in baseline and follow-up evaluations at Tel-Aviv Medical Center. NAFLD was determined by liver ultrasound or controlled attenuation parameter (CAP), and liver fibrosis was determined by FibroScan. Meat consumption (g/day) was assessed by a food frequency questionnaire (FFQ). In multivariable-adjusted analyses, high consumption of red and/or processed meat (≥gender-specific median) was associated with a higher risk of NAFLD with elevated alanine aminotransferase (ALT) (OR = 3.75, 1.21–11.62, p = 0.022). Consistently high (in both baseline and follow-up evaluations) total meat consumption was associated with 2.55-fold (95% CI 1.27–5.12, p = 0.009) greater odds for new onset and/or persistence of NAFLD compared to consistently low meat consumption. A similar association was shown for consistently high consumption of red and/or processed meat (OR = 2.12, 95% CI 1.11–4.05, p = 0.022). Consistently high red and/or processed meat consumption was associated with 4.77-fold (95% CI 1.36–16.69, p = 0.014) greater odds for significant fibrosis compared to consistently low consumption. Minimizing the consumption of red and/or processed meat may help prevent NAFLD and significant fibrosis.

Bariatric Surgery Improves Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis.

Bariatric surgery has been uncovered to relieve nonalcoholic fatty liver disease (NAFLD) in patients with obesity, while current studies have neutral or opposite results. This systematic review and meta-analysis aimed to evaluate the effects of bariatric surgery on NAFLD in patients with obesity. PubMed, Embase, Cochrane Central, and Web of Science databases were performed to obtain publications containing comparison results of liver biopsy before and after bariatric surgery in obesity. Primary outcomes were biopsy-confirmed remission of NAFLD and NAFLD activity scores. Secondary outcomes were liver function. This study was registered with PROSPERO, CRD42021240346. Thirty-seven studies were included. After bariatric surgery, a biopsy-confirmed resolution of steatosis was improved in 56% of patients, ballooning degeneration in 49%, inflammation in 45%, and fibrosis in 25%. Bariatric surgery significantly decreased mean NAFLD activity scores. RYGB achieved the most obviously improvements in steatosis, and SG attained the most notably ameliorations in fibrosis. The percentage of patients with improved steatosis and hepatic fibrosis in Asian countries was higher than non-Asian countries. The reduction of ALT and AST was 11.95U/L and 6.44 U/L after surgery. Our study has revealed that bariatric surgery brought out significantly resolution of NAFLD in individuals with obesity. RYGB and SG have been proved to be of benefit to many hepatic parameters, and the improvement of liver steatosis and fibrosis, particularly in Asian countries. It is strongly suggested that bariatric surgery should be considered as a novel treatment for NAFLD.

Bariatric Surgery is Effective and Safe for Obese Patients with Compensated Cirrhosis: A Systematic Review and Meta-Analysis.

With the global pandemic of obesity and nonalcoholic fatty liver disease (NAFLD), the incidence of cirrhosis associated with nonalcoholic steatohepatitis (NASH) has greatly increased. This study aimed to evaluate the efficacy and safety of bariatric surgery in obese cirrhotic patients. PubMed, EMBASE, and the Cochrane Library were searched for relevant studies. Effectiveness outcomes were weight loss, remission of comorbidities, and improvement in liver function. Safety outcomes were procedural complications and mortality. A total of 15 studies were included in this meta-analysis. Patients with compensated cirrhosis lost weight significantly after surgery, and the percentage of excess weight loss was 60.44 (95% CI, 44.34 to 76.55). Bariatric surgery resulted in remission of NAFLD in 57.9% (95% CI, 27.5% to 88.3%), T2DM in 58.4% (95% CI, 48.4% to 68.4%), hypertension in 53.1% (95% CI, 43% to 63.3%), dyslipidemia in 59.8% (95% CI, 41.1% to 78.5%) of patients with cirrhosis. Bariatric surgery reduced the levels of alanine aminotransferase and aspartate aminotransferase. The incidence of surgical complications in patients with cirrhosis was about 19.2% (95% CI, 11.7% to 26.6%), which was higher than that in patients without cirrhosis (OR 2.67 [95% CI, 1.26 to 5.67]). Patients with cirrhosis had an overall mortality rate of 1.3%, and the mortality rates for compensated cirrhosis and decompensated cirrhosis were 0.9% and 18.2%, respectively. Bariatric surgery is effective for weight loss, remission of comorbidities, and reversal of liver damage. Although cirrhotic patients have a higher risk of complications and death, bariatric surgery is relatively safe for well-compensated cirrhosis.

Inverse Association of Serum Adipsin with the Remission of Nonalcoholic Fatty-Liver Disease: A 3-Year Community-Based Cohort Study

Purposes: Adipokine alterations contribute to the development and remission of nonalcoholic fatty-liver disease (NAFLD). Adipsin is one of the most abundant adipokines and is almost exclusively produced by adipocytes. However, data on adipsin in human NAFLD are limited and controversial. We performed this study to investigate the association between adipsin and the remission of NAFLD in middle-aged and elderly Chinese adults. Methods: Whether adipsin is associated with the remission of NAFLD in a 3-year community-based prospective cohort study was investigated. Baseline levels of adipsin were measured in serum samples collected from 908 NAFLD participants. NAFLD was diagnosed using abdominal ultrasonography. Logistic regression analysis and a multiple stepwise logistic regression model including different variables were conducted to evaluate the association between serum adipsin levels and the remission of NAFLD. Results: During a mean follow-up of 3.14 ± 0.36 years, 247 (27.20%) participants with NAFLD at baseline were in remission. At baseline, serum adipsin concentration was positively correlated with body mass index (r: 0.39, p < 0.001), insulin (r: 0.31, p < 0.001), and homeostasis model assessment of insulin resistance (r: 0.31, p < 0.001) and was inversely associated with NAFLD remission with a fully adjusted odds ratio (OR) of 0.28 (0.16–0.48) (p trend < 0.001). In a multiple stepwise logistic regression model, circulating adipsin independently predicted NAFLD remission (OR: 0.284, 95% confidence interval [CI]: 0.172–0.471, p for trend <0.001). The area under the receiver operating characteristic curve was 0.751 (95% CI: 0.717–0.785) (p < 0.001) for the prediction model of NAFLD remission. Conclusions: We provide evidence for an association between serum adipsin levels and the remission of NAFLD in a community-based prospective cohort study. Serum adipsin can be a potential biomarker for predicting NAFLD remission.

Bariatric surgery for non-alcoholic fatty liver disease in individuals with obesity (Base-NAFLD): protocol of a prospective multicenter observational follow-up study

BackgroundBariatric surgery may be indicated in patients with nonalcoholic fatty liver disease (NAFLD) to achieve and maintain the degree of weight loss required to ensure therapeutic effects. However, bariatric surgery is still underrecognized in the treatment of NAFLD, including its inflammatory subtype, nonalcoholic steatohepatitis (NASH). Moreover, there is a lack of follow-up outcome data on different types of bariatric surgery in patients with NAFLD. This study aims to adequately assess the effect of bariatric surgery on NAFLD remission in obese patients.MethodsThis prospective multicentre observational follow-up study will include 142 obese patients with NAFLD scheduled to undergo one of the following surgical procedures: sleeve gastrostomy, Roux-en-Y gastric bypass, and one anastomosis gastric bypass. The primary outcome is the complete remission rate of NAFLD one year postoperatively, which is defined by liver fat fraction < 5% on magnetic resonance imaging; the secondary outcomes includes (i) changes in NASH and liver fibrosis biopsy findings, (ii) changes in body weight and abdominal adipose weight, (iii) resolution of obesity-related comorbidities, and (iv) incidence of adverse events. A long-term follow-up related to this study will also be conducted.DiscussionThis study will provide a necessary and preliminary foundation for the early identification and targeted treatment of patients with NAFLD who can be referred for bariatric surgery, as indicated for management of obesity and metabolic disease.Trial registration: Clinicaltrials.gov: NCT04366999. Registered 21 April 2020. (https://clinicaltrials.gov/ct2/show/NCT04366999).

Predictors for incidence and remission of nonalcoholic fatty liver disease in obese children and adolescents

The status of nonalcoholic fatty liver disease (NAFLD) can wax and wane over time in children. However, the factors affecting its incidence and remission remain elusive. We aimed to investigate NAFLD incidence, remission and predicting factors in obese children. Obese children aged 9-10 and 12-13 years were recruited from schools and followed up for 2 years. Liver ultrasonography was performed at baseline and Year 1. Alanine aminotransferase (ALT) concentrations were measured at baseline, Year 1 and Year 2. Elevated ALT was defined as above 26 U/L for boys and 22 U/L for girls. Four NAFLD susceptible genes, including PNPLA3, GCKR, TM6SF2 and MBOAT7, were genotyped. We analyzed the effects of these risk factors on the incidence and remission of NAFLD and elevated ALT. At baseline, 86 of 440 (19.5%) subjects had ultrasonography-diagnosed NAFLD. At Year 1, of 264 subjects without NAFLD at baseline, 20 (7.6%) developed NAFLD. The baseline BMI z-score and increment in BMI z-score independently predicted incident NAFLD. Of the 68 subjects with NAFLD at baseline, 36 (52.9%) had NAFLD remission. Decrement in BMI z-score independently predicted NAFLD remission. The four studied NAFLD susceptible genes were not significantly associated with either the incidence or remission of NAFLD. In addition, changes in BMI z-score predicted the incidence and remission of elevated ALT from Year 1 to Year 2. Obese children with increasing BMI are more likely to develop NAFLD and those with decreasing BMI are more likely to have NAFLD remission.

Osteocalcin and Non-Alcoholic Fatty Liver Disease: Lessons From Two Population-Based Cohorts and Animal Models.

Osteocalcin regulates energy metabolism in an active undercarboxylated/uncarboxylated form. However, its role on the development of non-alcoholic fatty liver disease (NAFLD) is still controversial. In the current study, we investigated the causal relationship of circulating osteocalcin with NAFLD in two human cohorts and studied the effect of uncarboxylated osteocalcin on liver lipid metabolism through animal models. We analyzed the correlations of serum total/uncarboxylated osteocalcin with liver steatosis/fibrosis in a liver biopsy cohort of 196 participants, and the causal relationship between serum osteocalcin and the incidence/remission of NAFLD in a prospective community cohort of 2055 subjects from Shanghai Changfeng Study. Serum total osteocalcin was positively correlated with uncarboxylated osteocalcin (r = 0.528, p < .001). Total and uncarboxylated osteocalcin quartiles were inversely associated with liver steatosis, inflammation, ballooning, and fibrosis grades in both male and female participants (all p for trend <.05). After adjustment for confounding glucose, lipid, and bone metabolism parameters, the male and female participants with lowest quartile of osteocalcin still had more severe liver steatosis, with multivariate-adjusted odds ratios (ORs) of 7.25 (1.07-49.30) and 4.44 (1.01-19.41), respectively. In the prospective community cohort, after a median of 4.2-year follow-up, the female but not male participants with lowest quartile of osteocalcin at baseline had higher risk to develop NAFLD (hazard ratio [HR] = 1.90; 95% confidence interval [CI] 1.14-3.16) and lower chance to achieve NAFLD remission (HR = 0.56; 95% CI 0.31-1.00). In wild-type mice fed a Western diet, osteocalcin treatment alleviated hepatic steatosis and reduced hepatic SREBP-1 and its downstream proteins expression. In mice treated with osteocalcin for a short term, hepatic SREBP-1 expression was decreased without changes of glucose level or insulin sensitivity. When SREBP-1c was stably expressed in a human SREBP-1c transgenic rat model, the reduction of lipogenesis induced by osteocalcin treatment was abolished. In conclusion, circulating osteocalcin was inversely associated with NAFLD. Osteocalcin reduces liver lipogenesis via decreasing SREBP-1c expression. © 2020 American Society for Bone and Mineral Research (ASBMR).

Effect of weight change and lifestyle modifications on the development or remission of nonalcoholic fatty liver disease: sex-specific analysis

The effects of changes in various lifestyle habits on nonalcoholic fatty liver disease (NAFLD) have not been well elucidated. We aimed to clarify how weight change and lifestyle modifications were associated with the development or remission of NAFLD. In this longitudinal cohort study, we reviewed the periodic health checkup data of 1,421 subjects with no causes of liver disease besides NAFLD who had received at least two health checkups between 2009 and 2018. The prevalence of NAFLD at baseline was 34.1% (484/1,421). During follow-up period (4.6 ± 2.8 years), 104 subjects developed NAFLD and 127 subjects demonstrated NAFLD remission. The frequency of NAFLD development or that of NAFLD remission significantly increased as the larger weight gain or weight loss was, respectively (both, p < 0.001). Approximately 40% of the subjects who maintained ≥ 1%/year weight loss achieved NAFLD remission. By multivariate analysis, quitting smoking were independently associated with NAFLD development (adjusted odds ratio [AOR], 2.86; 95% CI, 1.24–6.62). Subjects who quit smoking demonstrated large weight gain (≥1%/year) significantly more frequently than the other subjects (p < 0.001). In sex-specific analysis, starting to exercise was independently associated with NAFLD remission in men (AOR, 2.38; 95% CI, 1.25–4.53).

Role of intensive dietary and lifestyle interventions in the treatment of lean nonalcoholic fatty liver disease patients.

Although weight loss is recommended for the treatment of nonalcoholic fatty liver disease (NAFLD) in overweight and obese individuals, this treatment modality remains questionable in lean individuals. In this study, we investigated the effects of medical nutrition therapy (MNT) and intensive lifestyle interventions (ILIs) for NAFLD in lean versus obese patients. In total, 35 patients (14 lean and 21 obese) were included in the study. All patients underwent transient elastography examinations, and controlled attenuation parameter (CAP) of >238 dB/m was indicative of hepatic steatosis. After 8 weeks of dietitian follow-up with MNT and ILI, the patients were compared with the baseline. Significant weight loss was recorded in both lean (5.4%) and obese patients (5.7%) with NAFLD. The mean BMI decreased from 23.9 (20.5-24.8) to 22.4 (19.5-24.2) kg/m (P = 0.001) in lean patients and from 34.0 (30.0-42.0) to 31.6 (26.9-42.5) kg/m (P < 0.001) in obese patients. The alanine aminotransferase level significantly decreased from 56 (15-163) to 28 (13-98) U/L (P = 0.010) in lean patients and from 27 (13-81) to 22 (13-46) U/L (P = 0.018) in obese patients. The median CAP decreased from 299 (246-360) to 236 (169-318) dB/m (P = 0.002) in lean patients and from 325 (258-400) to 253 (202-383) dB/m (P < 0.001) in obese patients. Moreover, remission of hepatic steatosis was detected in eight lean patients (57.1%) and eight obese patients (38.1%). These results indicate that 5% body weight loss in effective in both obese and lean patients resulting in a similar NAFLD remission.

Free triiodothyronine is associated with the occurrence and remission of nonalcoholic fatty liver disease in euthyroid women.

The association between nonalcoholic fatty liver disease (NAFLD) and free triiodothyronine (FT3) in euthyroid subjects was in dispute. We aimed to investigate this issue in a population-based cohort study. A total of 3144 euthyroid subjects at baseline from the Shanghai Nicheng Atherosclerosis Study were selected for the cross-sectional analysis, and 2089 subjects being followed up after 2.2years were selected for the longitudinal analysis. NAFLD was diagnosed by ultrasound. The cut-off point of elevated alanine aminotransferase (ALT) level was 40U/L. The FIB-4 index was used to assess the risk of advanced liver fibrosis. Age-adjusted mean levels of FT3 and FT3/free thyroxine (FT4) ratio were higher in subjects with NAFLD than those without NAFLD and linearly increased with a higher risk of NAFLD progression (assessed by levels of ALT and FIB-4 index) in euthyroid women but not in men. After adjustment for confounding variables, FT3 levels significantly increased with the presence of NAFLD (β=0.1, P<0.001) and linearly increased with a higher risk of NAFLD progression in euthyroid women. After a 2.2-year follow-up, FT3 levels increased with the occurrence of NAFLD (mean change percentage: 1.4%) and decreased with the remission of NAFLD (mean change percentage: -2.7%) in euthyroid women. There are positive associations of FT3 levels with NAFLD and the risk of NAFLD progression in euthyroid women. The changes in FT3 levels with the alteration of NAFLD status may be an adaptive response to maintain energy and metabolic homeostasis.