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The Effect of High-intensity Interval Training vs Moderate-intensity Continuous Training on Liver Fat: A Systematic Review and Meta-Analysis.
Sabag, A, Barr, L, Armour, M, Armstrong, A, Baker, CJ, Twigg, SM, Chang, D, Hackett, DA, Keating, SE, George, J, et al
The Journal of clinical endocrinology and metabolism. 2022;(3):862-881
Abstract
CONTEXT Non-alcoholic fatty liver disease, characterized by excess fat accumulation in the liver, is considered the hepatic manifestation of metabolic syndrome. Recent findings have shown that high-intensity interval training (HIIT) can reduce liver fat but it is unclear whether this form of exercise is superior to traditional moderate-intensity continuous training (MICT). OBJECTIVE The aim of this systematic review was to determine the effect of HIIT vs MICT on liver fat in adults. A secondary aim was to investigate the interaction between total weekly exercise volume and exercise-related energy expenditure and change in liver fat. METHODS Relevant databases were searched up to December 2020 for randomized trials, comparing HIIT to control, MICT to control, or HIIT to MICT. Studies were excluded if they did not implement 2 or more weeks' intervention or assess liver fat using magnetic resonance-based techniques. Weighted mean differences and 95% CIs were calculated. Regression analyses were undertaken to determine the interaction between weekly exercise volume in minutes and kilocalories (kcal) with change in liver fat content. RESULTS Of the 28 268 studies screened, 19 were included involving 745 participants. HIIT and MICT both elicited moderate reductions in liver fat content when compared to control (HIIT: -2.85%, 95% CI, -4.86 to -0.84, P = .005, I2 = 0%, n = 114, low-certainty evidence; MICT -3.14%, 95% CI, -4.45 to -1.82, P < .001, I2 = 5.2%, n = 533, moderate-certainty evidence). There was no difference between HIIT and MICT (-0.34%, 95% CI, -2.20 to 1.52, P = .721, I2 = 0%, n = 177, moderate-certainty evidence). Neither total exercise volume in minutes (β = .0002, SE = 0.0017, Z = 0.13, P = .89) nor exercise-related energy expenditure in kcal (β = .0003, SE = 0.0002, Z = 1.21, P = .23) were related to changes in liver fat content. CONCLUSION HIIT elicits comparable improvements in liver fat to MICT despite often requiring less energy and time commitment. Further studies should be undertaken to assess the relative importance of aerobic exercise prescription variables, such as intensity, on liver fat.
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Insight of the role of mitochondrial calcium homeostasis in hepatic insulin resistance.
Dong, Z, Yao, X
Mitochondrion. 2022;:128-138
Abstract
Due to the rapid rise in the prevalence of chronic metabolic disease, more and more clinicians and basic medical researchers focus their eyesight on insulin resistance (IR), an early and central event of metabolic diseases. The occurrence and development of IR are primarily caused by excessive energy intake and reduced energy consumption. Liver is the central organ that controls glucose homeostasis, playing a considerable role in systemic IR. Decreased capacity of oxidative metabolism and mitochondrial dysfunction are being blamed as the direct reason for the development of IR. Mitochondrial Ca2+ plays a fundamental role in maintaining proper mitochondrial function and redox stability. The maintaining of mitochondrial Ca2+ homeostasis requires the cooperation of ion channels in the inner and outer membrane of mitochondria, such as mitochondrial calcium uniporter complex (MCUC) and voltage-dependent anion channels (VDACs). In addition, the crosstalk between the endoplasmic reticulum (ER), lysosome and plasma membrane with mitochondria is also significant for mitochondrial calcium homeostasis, which is responsible for an efficient network of cellular Ca2+ signaling. Here, we review the recent progression in the research about the regulation factors for mitochondrial Ca2+ and how the dysregulation of mitochondrial Ca2+ homeostasis is involved in the pathogenesis of hepatic IR, providing a new perspective for further exploring the role of ion in the onset and development of IR.
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Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease.
Negi, CK, Babica, P, Bajard, L, Bienertova-Vasku, J, Tarantino, G
Metabolism: clinical and experimental. 2022;:154925
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. With no Food and Drug Administration approved drugs, current treatment options include dietary restrictions and lifestyle modification. NAFLD is closely associated with metabolic disorders such as obesity, type 2 diabetes, and dyslipidemia. Hence, clinically various pharmacological approaches using existing drugs such as antidiabetic, anti-obesity, antioxidants, and cytoprotective agents have been considered in the management of NAFLD and nonalcoholic steatohepatitis (NASH). However, several pharmacological therapies aiming to alleviate NAFLD-NASH are currently being examined at various phases of clinical trials. Emerging data from these studies with drugs targeting diverse molecular mechanisms show promising outcomes. This review summarizes the current understanding of the pathogenic mechanisms of NAFLD and provides an insight into the pharmacological targets and emerging therapeutics with specific interventional mechanisms. In addition, we also discuss the importance and utility of new approach methodologies and regulatory perspectives for NAFLD-NASH drug development.
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Prognostic value of baseline imaging and clinical features in patients with advanced hepatocellular carcinoma.
Öcal, O, Ingrisch, M, Ümütlü, MR, Peynircioglu, B, Loewe, C, van Delden, O, Vandecaveye, V, Gebauer, B, Zech, CJ, Sengel, C, et al
British journal of cancer. 2022;(2):211-218
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Abstract
AIMS: To investigate the prognostic value of baseline imaging features for overall survival (OS) and liver decompensation (LD) in patients with hepatocellular carcinoma (HCC). DESIGN Patients with advanced HCC from the SORAMIC trial were evaluated in this post hoc analysis. Several radiological imaging features were collected from baseline computed tomography (CT) and magnetic resonance imaging (MRI) imaging, besides clinical values. The prognostic value of these features for OS and LD (grade 2 bilirubin increase) was quantified with univariate Cox proportional hazard models and multivariate Least Absolute Shrinkage and Selection Operator (LASSO) regression. RESULTS Three hundred and seventy-six patients were included in this study. The treatment arm was not correlated with OS. LASSO showed satellite lesions, atypical HCC, peritumoral arterial enhancement, larger tumour size, higher albumin-bilirubin (ALBI) score, liver-spleen ratio <1.5, ascites, pleural effusion and higher bilirubin values were predictors of worse OS, and higher relative liver enhancement, smooth margin and capsule were associated with better OS. LASSO analysis for LD showed satellite lesions, peritumoral hypointensity in hepatobiliary phase, high ALBI score, higher bilirubin values and ascites were predictors of LD, while randomisation to sorafenib arm was associated with lower LD. CONCLUSIONS Imaging features showing aggressive tumour biology and poor liver function, in addition to clinical parameters, can serve as imaging biomarkers for OS and LD in patients receiving sorafenib and selective internal radiation therapy for HCC.
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Determinants of hepatic insulin clearance - Results from a Mendelian Randomization study.
Lamprinou, A, Willmann, C, Machann, J, Schick, F, Eckstein, SS, Dalla Man, C, Visentin, R, Birkenfeld, AL, Peter, A, Stefan, N, et al
Metabolism: clinical and experimental. 2021;:154776
Abstract
AIMS/HYPOTHESIS Besides insulin resistance, type 2 diabetes associates with decreased hepatic insulin clearance (HIC). We now tested for causal relationship of HIC to liver fat accumulation or features of the metabolic syndrome. METHODS HIC was derived from oral glucose tolerance tests with the "Oral C-peptide and Insulin Minimal Models" (n = 3311). Liver fat was quantified by magnetic resonance spectroscopy (n = 1211). Mendelian Randomization was performed using established single nucleotide polymorphisms (SNPs; 115 for liver fat, 155 alanine-aminotransferase, 37 insulin sensitivity, 37 insulin secretion, 72 fasting insulin, 5285 BMI, 163 visceral fat, 270 waist circumference, 442 triglycerides, 620 HDL-Cholesterol, 193 C-reactive protein, 53 lipodystrophy-like phenotypes). RESULTS HIC associated inversely with liver fat (p < 0.003) and insulin sensitivity (p < 0.0001). Both liver fat and HIC were independently associated with insulin sensitivity (p < 0.0001). Neither liver fat nor alanine-aminotransferase were causally linked to HIC, as indicated by Mendelian Randomization (Nliver fat = 1054, NHIC = 2254; Nalanineaminotranferase = 1985, NHIC = 2251). BMI-related SNPs were causally associated with HIC (NBMI = 2772, NHIC = 2259, p < 0.001) but not waist circumference-SNPs (NSNPs-waist circumference = 2751, NHIC = 2280). Genetically determined insulin sensitivity was not causally related to HIC (Ninsulin sensitivity = 2752, NHIC = 2286). C-reactive protein and HDL were causally associated with HIC, with higher C-reactive protein and lower HDL leading to higher HIC (NC-reactive protein = 2660, NHIC = 2240; NHDL = 2694, NHIC = 2275). CONCLUSIONS This Mendelian Randomization analysis does not support a causal link between hepatic steatosis and HIC. Other components of the metabolic syndrome seem to compensate peripheral hyperinsulinemia by increasing hepatic insulin extraction.
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Bariatric Surgery and Liver Disease: General Considerations and Role of the Gut-Liver Axis.
Cerreto, M, Santopaolo, F, Gasbarrini, A, Pompili, M, Ponziani, FR
Nutrients. 2021;(8)
Abstract
Weight loss is a therapeutic solution for many metabolic disorders, such as obesity and its complications. Bariatric surgery aims to achieve lasting weight loss in all patients who have failed after multiple dietary attempts. Among its many benefits, it has been associated with the regression of non-alcoholic fatty liver disease (NAFLD), which is often associated with obesity, with evidence of substantial improvement in tissue inflammation and fibrosis. These benefits are mediated not only by weight loss, but also by favorable changes in systemic inflammation and in the composition of the gut microbiota. Changes in microbial metabolites such as short-chain fatty acids (SCFAs), capable of acting as endocrine mediators, and bile acids (BAs) as well as modifications of the gut-brain axis, are among the involved mechanisms. However, not all bariatric surgeries show beneficial effects on the liver; those leading to malabsorption can cause liver failure or a marked worsening of fibrosis and the development of cirrhosis. Nevertheless, there are still many unclear aspects, including the extent of the benefits and the magnitude of the risks of bariatric surgery in cirrhotic patients. In addition, the usefulness and the safety of these procedures in patients who are candidates to or who have undergone liver transplant need solid supporting evidence. This paper aims to review literature data on the use of bariatric surgery in the setting of chronic liver disease.
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Metabolism of sugars: A window to the regulation of glucose and lipid homeostasis by splanchnic organs.
Tappy, L
Clinical nutrition (Edinburgh, Scotland). 2021;(4):1691-1698
Abstract
BACKGROUND &AIMS: Dietary sugars are absorbed in the hepatic portal circulation as glucose, fructose, or galactose. The gut and liver are required to process fructose and galactose into glucose, lactate, and fatty acids. A high sugar intake may favor the development of cardio-metabolic diseases by inducing Insulin resistance and increased concentrations of triglyceride-rich lipoproteins. METHODS A narrative review of the literature regarding the metabolic effects of fructose-containing sugars. RESULTS Sugars' metabolic effects differ from those of starch mainly due to the fructose component of sucrose. Fructose is metabolized in a set of fructolytic cells, which comprise small bowel enterocytes, hepatocytes, and kidney proximal tubule cells. Compared to glucose, fructose is readily metabolized in an insulin-independent way, even in subjects with diabetes mellitus, and produces minor increases in glycemia. It can be efficiently used for energy production, including during exercise. Unlike commonly thought, fructose when ingested in small amounts is mainly metabolized to glucose and organic acids in the gut, and this organ may thus shield the liver from potentially deleterious effects. CONCLUSIONS The metabolic functions of splanchnic organs must be performed with homeostatic constraints to avoid exaggerated blood glucose and lipid concentrations, and thus to prevent cellular damages leading to non-communicable diseases. Excess fructose intake can impair insulin-induced suppression of glucose production, stimulate de novo lipogenesis, and increase intrahepatic and blood triglyceride concentrations. With chronically high fructose intake, enterocyte can switch to lipid synthesis and accumulation of triglyceride, possibly causing an enterocyte dysfunction.
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Reenvisioning Traditional to Regenerative Therapeutic Advances in Managing Nonalcoholic Fatty Liver Disease in Diabetes Mellitus.
Tsai, LW, Lu, YH, Dubey, R, Chiou, JF
Journal of diabetes research. 2021;:7692447
Abstract
Reports indicate the increasing prevalence of liver disorders in diabetes mellitus (DM) patients. Clinically, it has also been revealed that the existence of nonalcoholic fatty liver disease (NAFLD) enhances the incidence of type 2 diabetes mellitus (T2DM), while T2DM exacerbates NAFLD to extremely severe forms of steatohepatitis, cirrhosis, and hepatocellular carcinoma. This implies the coexistence and bidirectional nature of NAFLD and T2DM, which function synergistically to drive adverse consequences in clinical practice. For treatment of such comorbid state, though the existing practices such as lifestyle management, traditional Chinese medicines (TCM), and pharmaceuticals have offered somewhat relief, the debate continues about the optimal therapeutic impacts. Recent developments in the field of tissue engineering have led to a renewed interest in novel biomaterial alternatives such as stem cells. This might be attributable to their differentiation potential towards hepatic and pancreatic lineage. These cellular therapies could be further complemented by platelet-derived biomaterials, TCM formulations, or any specific drug. Based on these abovementioned approaches, we aimed to comprehensively analyze various preclinical and clinical studies from traditional to regenerative therapeutic approaches in managing concomitant NAFLD and T2DM.
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Fetuin-B, a potential link of liver-adipose tissue cross talk during diet-induced weight loss-weight maintenance.
Li, L, Spranger, L, Stobäus, N, Beer, F, Decker, AM, Wernicke, C, Brachs, S, Brachs, M, Spranger, J, Mai, K
Nutrition & diabetes. 2021;(1):31
Abstract
BACKGROUND/OBJECTIVES Numerous hepatokines are involved in inter-organ cross talk regulating tissue-specific insulin sensitivity. Adipose tissue lipolysis represents a crucial element of adipose insulin sensitivity and is substantially involved in long-term body weight regulation after dietary weight loss. Thus, we aimed to analyze the impact of the hepatokine Fetuin-B in the context of weight loss induced short- and long-term modulation of adipose insulin sensitivity. SUBJECTS/METHODS 143 subjects (age > 18; BMI ≥ 27 kg/m2) were analyzed before (T-3) and after (T0) a standardized 12-week dietary weight reduction program. Afterward, subjects were randomized to a 12-month lifestyle intervention or a control group. After 12 months (T12) no further intervention was performed until 6 months later (T18) (Maintain-Adults trial). Tissue-specific insulin sensitivity was estimated by HOMA-IR (predominantly liver), ISIClamp (predominantly skeletal muscle), and free fatty acid suppression during hyperinsulinemic-euglycemic clamp (FFASupp) (predominantly adipose tissue). Fetuin-B was measured at all concomitant time points. RESULTS Circulating Fetuin-B levels correlated significantly with estimates of obesity, hepatic steatosis as well as HOMA-IR, ISIClamp, FFASupp at baseline. Fetuin-B decreased during dietary weight loss (4.2 (3.5-4.9) vs. 3.8 (3.2-4.6) µg/ml; p = 2.1 × 10-5). This change was associated with concomitant improvement of HOMA-IR (r = 0.222; p = 0.008) and FFASupp (r = -0.210; p = 0.013), suggesting a particular relationship to hepatic and adipose tissue insulin sensitivity. Weight loss induced improvements of insulin resistance were almost completely preserved until months 12 and 18 and most interestingly, the short and long-term improvement of FFASupp was partially predicted by baseline level of Fetuin-B. CONCLUSIONS Our data suggest that Fetuin-B might be a potential mediator of liver-adipose cross talk involved in short- and long-term regulation of adipose insulin sensitivity, especially in the context of diet-induced weight changes. TRIAL REGISTRATION ClinicalTrials.gov number: NCT00850629, https://clinicaltrials.gov/ct2/show/NCT00850629 , date of registration: February 25, 2009.
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Impact of prolonged fasting on insulin secretion, insulin action, and hepatic versus whole body insulin secretion disposition indices in healthy young males.
Jørgensen, SW, Hjort, L, Gillberg, L, Justesen, L, Madsbad, S, Brøns, C, Vaag, AA
American journal of physiology. Endocrinology and metabolism. 2021;(2):E281-E290
Abstract
The extent to which reduced insulin secretion during prolonged fasting reflects failure to compensate for whole body insulin resistance or a normal adjustment to potentially increased hepatic insulin action is unknown. We examined the effects of 36- versus 12-h fasting on insulin secretion and whole body versus hepatic insulin action in 13 healthy young males. Hepatic glucose production and insulin action were studied using stable isotopes, whereas whole body insulin action and insulin secretion were studied using an intravenous glucose tolerance test (IVGTT) and minimal modeling. Insulin, glucose, and lipid profiles were subsequently measured during a refeeding meal test. Prolonged fasting caused a minor reduction of first-phase insulin secretion in a context of improved hepatic insulin action, contrasting an increase in whole body insulin resistance. Accordingly, prolonged fasting was associated with opposite-directed effects on hepatic versus whole body insulin secretion disposition indices. Thirty-six-hour fasting compared with 12-h fasting was associated with increased serum insulin levels during the refeeding meal test. In conclusion, reduced insulin secretion during prolonged fasting may represent a healthy response to improved hepatic insulin action. Use of insulin secretion disposition indices without taking organ-specific insulin action into account may lead to erroneous conclusions.NEW & NOTEWORTHY Thirty-six-hour prolonged, compared with 12-h overnight fasting, is associated with slightly reduced first-phase insulin secretion in the face of opposite-directed changes in hepatic versus whole body insulin action in healthy young males. The paradoxical finding of increased hepatic versus decreased whole body insulin secretion disposition indices during prolonged fasting challenges the physiological understanding and validity of insulin secretion disposition indices not taking organ-specific insulin action into account.