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1.
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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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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Liver, Oxidative Stress and Metabolic Syndromes.
Rezzani, R, Franco, C
Nutrients. 2021;(2)
Abstract
Today, talking about metabolic syndrome (MetS) and oxidative stress, can be risky [...].
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Liver fat scores do not reflect interventional changes in liver fat content induced by high-protein diets.
Kabisch, S, Markova, M, Hornemann, S, Sucher, S, Pivovarova-Ramich, O, Machann, J, Hierholzer, J, Rohn, S, Pfeiffer, AFH
Scientific reports. 2021;(1):8843
Abstract
Non-alcoholic fatty liver disease (NAFLD) is common in Metabolic Syndrome and type 2 diabetes (T2DM), driven by energy imbalance, saturated fats and simple carbohydrates. NAFLD requires screening and monitoring for late complications. Liver fat indices may predict NAFLD avoiding expensive or invasive gold-standard methods, but they are poorly validated for use in interventional settings. Recent data indicate a particular insensitivity to weight-independent liver fat reduction. We evaluated 31 T2DM patients, completing a randomized intervention study on isocaloric high-protein diets. We assessed anthropometric measures, intrahepatic lipid (IHL) content and serum liver enzymes, allowing AUROC calculations as well as cross-sectional and longitudinal Spearman correlations between the fatty liver index, the NAFLD-liver fat score, the Hepatosteatosis Index, and IHL. At baseline, all indices predicted NAFLD with moderate accuracy (AUROC 0.731-0.770), supported by correlation analyses. Diet-induced IHL changes weakly correlated with changes of waist circumference, but no other index component or the indices themselves. Liver fat indices may help to easily detect NAFLD, allowing cost-effective allocation of further diagnostics to patients at high risk. IHL reduction by weight-independent diets is not reflected by a proportional change in liver fat scores. Further research on the development of treatment-sensitive indices is required.Trial registration: The trial was registered at clinicaltrials.gov: NCT02402985.
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Role of growth hormone in hepatic and intestinal triglyceride-rich lipoprotein metabolism.
Maraninchi, M, Calabrese, A, Nogueira, JP, Castinetti, F, Mancini, J, Mourre, F, Piétri, L, Bénamo, E, Albarel, F, Morange, I, et al
Journal of clinical lipidology. 2021;(5):712-723
Abstract
BACKGROUND Elevated plasma concentrations of hepatic- and intestinally-derived triglyceride-rich lipoproteins (TRL) are implicated in the pathogenesis of atherosclerotic cardiovascular disease and all-cause mortality. Excess of TRL is the driving cause of atherogenic dyslipidemia commonly occurring in insulin-resistant individuals such as patients with obesity, type 2 diabetes and metabolic syndrome. Interestingly, growth hormone (GH)-deficient individuals display similar atherogenic dyslipidemia, suggesting an important role of GH and GH deficiency in the regulation of TRL metabolism. OBJECTIVE We aimed to examine the direct and/or indirect role of GH on TRL metabolism. METHODS We investigated the effect on fasting and postprandial hepatic-TRL and intestinal-TRL metabolism of short-term (one month) withdrawal of GH in 10 GH-deficient adults. RESULTS After GH withdrawal, we found a reduction in fasting plasma TRL concentration (significant decrease in TRL-TG, TRL-cholesterol, TRL-apoB-100, TRL-apoC-III and TRL-apoC-II) but not in postprandial TRL response. This reduction was due to fewer fasting TRL particles without a change in TG per particle and was not accompanied by a change in postprandial TRL-apoB-48 response. Individual reductions in TRL correlated strongly with increases in insulin sensitivity and decreases in TRL-apoC-III. CONCLUSION In this relatively short term 'loss of function' human experimental model, we have shown an unanticipated reduction of hepatic-TRL particles despite increase in total body fat mass and reduction in lean mass. These findings contrast with the atherogenic dyslipidemia previously described in chronic GH deficient states, providing a new perspective for the role of GH in lipoprotein metabolism.
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6.
Nonalcoholic Steatohepatitis: A Review.
Sheka, AC, Adeyi, O, Thompson, J, Hameed, B, Crawford, PA, Ikramuddin, S
JAMA. 2020;(12):1175-1183
Abstract
IMPORTANCE Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of nonalcoholic fatty liver disease (NAFLD) and is associated with disease progression, development of cirrhosis, and need for liver transplant. Despite its importance, NASH is underrecognized in clinical practice. OBSERVATIONS NASH affects an estimated 3% to 6% of the US population and the prevalence is increasing. NASH is strongly associated with obesity, dyslipidemia, type 2 diabetes, and metabolic syndrome. Although a number of noninvasive tests and scoring systems exist to characterize NAFLD and NASH, liver biopsy is the only accepted method for diagnosis of NASH. Currently, no NASH-specific therapies are approved by the US Food and Drug Administration. Lifestyle modification is the mainstay of treatment, including dietary changes and exercise, with the primary goal being weight loss. Substantial improvement in histologic outcomes, including fibrosis, is directly correlated with increasing weight loss. In some cases, bariatric surgery may be indicated to achieve and maintain the necessary degree of weight loss required for therapeutic effect. An estimated 20% of patients with NASH will develop cirrhosis, and NASH is predicted to become the leading indication for liver transplants in the US. The mortality rate among patients with NASH is substantially higher than the general population or patients without this inflammatory subtype of NAFLD, with annual all-cause mortality rate of 25.56 per 1000 person-years and a liver-specific mortality rate of 11.77 per 1000 person-years. CONCLUSIONS AND RELEVANCE Nonalcoholic steatohepatitis affects 3% to 6% of the US population, is more prevalent in patients with metabolic disease and obesity, progresses to cirrhosis in approximately 20% of cases, and is associated with increased rates of liver-specific and overall mortality. Early identification and targeted treatment of patients with nonalcoholic steatohepatitis are needed to improve patient outcomes, including directing patients toward intensive lifestyle modification to promote weight loss and referral for bariatric surgery as indicated for management of obesity and metabolic disease.
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Circulating PCSK9 is associated with liver biomarkers and hepatic steatosis.
Paquette, M, Gauthier, D, Chamberland, A, Prat, A, De Lucia Rolfe, E, Rasmussen, JJ, Kaduka, L, Seidah, NG, Bernard, S, Christensen, DL, et al
Clinical biochemistry. 2020;:20-25
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Abstract
BACKGROUND In parallel to the increasing prevalence of metabolic syndrome, the prevalence of hepatic steatosis has also increased dramatically worldwide. Hepatic steatosis is a major risk factor of hepatic cirrhosis, cardiovascular disease and type 2 diabetes. Circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) have been positively associated with the metabolic syndrome. However, the association between PCSK9 and the liver function is still controversial. OBJECTIVE The objective of this study is to investigate the association between circulating PCSK9 levels and the presence of hepatic steatosis, as well as with liver biomarkers in a cohort of healthy individuals. METHODS Total PCSK9 levels were measured by an in-house ELISA using a polyclonal antibody. Plasma albumin, alkaline phosphatase, ALT, AST, total bilirubin and GGT were measured in 698 individuals using the COBAS system. The presence of hepatic steatosis was assessed using ultrasound liver scans. RESULTS In a multiple regression model adjusted for age, sex, insulin resistance, body mass index and alcohol use, circulating PCSK9 level was positively associated with albumin (β = 0.102, P = 0.008), alkaline phosphatase (β = 0.201, P < 0.0001), ALT (β = 0.238, P < 0.0001), AST (β = 0.120, P = 0.003) and GGT (β = 0.103, P = 0.007) and negatively associated with total bilirubin (β = -0.150, P < 0.0001). Tertile of circulating PCSK9 was also associated with hepatic steatosis (OR 1.48, 95% CI 1.05-2.08, P = 0.02). CONCLUSION Our data suggest a strong association between PCSK9 and liver biomarkers as well as hepatic steatosis. Further studies are needed to explore the role of PCSK9 on hepatic function.
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Beyond Body Weight-Loss: Dietary Strategies Targeting Intrahepatic Fat in NAFLD.
Worm, N
Nutrients. 2020;(5)
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent liver disease in industrialized countries. It is regarded as the hepatic manifestation of the metabolic syndrome (MetS) resulting from insulin resistance. Moreover, insulin resistance impairs glycogen synthesis, postprandially diverting a substantial amount of carbohydrates to the liver and storing them there as fat. NAFLD has far-reaching metabolic consequences involving glucose and lipoprotein metabolism disorders and risk of cardiovascular disease, the leading cause of death worldwide. No pharmaceutical options are currently approved for the treatment of NAFLD. Exercise training and dietary interventions remain the cornerstone of NAFLD treatment. Current international guidelines state that the primary goal of nutritional therapy is to reduce energy intake to achieve a 7%-10% reduction in body weight. Meal replacement therapy (formula diets) results in more pronounced weight loss compared to conventional calorie-restricted diets. However, studies have shown that body mass index (BMI) or weight reduction is not obligatory for decreasing hepatic fat content or to restore normal liver function. Recent studies have achieved significant reductions in liver fat with eucaloric diets and without weight loss through macronutrient modifications. Based on this evidence, an integrative nutritional therapeutic concept was formulated that combines the most effective nutrition approaches termed "liver-fasting." It involves the temporary use of a low calorie diet (total meal replacement with a specific high-protein, high-soluble fiber, lower-carbohydrate formula), followed by stepwise food reintroduction that implements a Mediterranean style low-carb diet as basic nutrition.
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Range of Normal Liver Stiffness and Factors Associated With Increased Stiffness Measurements in Apparently Healthy Individuals.
Bazerbachi, F, Haffar, S, Wang, Z, Cabezas, J, Arias-Loste, MT, Crespo, J, Darwish-Murad, S, Ikram, MA, Olynyk, JK, Gan, E, et al
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2019;(1):54-64.e1
Abstract
BACKGROUND & AIMS Transient elastography (TE) is a noninvasive technique used to measure liver stiffness to estimate the severity of fibrosis. The range of liver stiffness measurements (LSMs) in healthy individuals is unclear. We performed a systematic review to determine the range of LSMs, examined by TE, in healthy individuals and individuals who are susceptible to fibrosis. METHODS We collected data from 16,082 individuals, in 26 cohorts, identified from systematic searches of Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for studies of liver stiffness measurements. Studies analyzed included apparently healthy adults (normal levels of liver enzymes, low-risk alcohol use patterns, and negative for markers of viral hepatitis). The presence of diabetes, hypertension, dyslipidemia, or steatosis, based on ultrasound examination, was known for most participants. We performed a meta-analysis of data from individual participants. The cohort was divided into 4 groups; participants with a body mass index <30 kg/m2 were examined with the medium probe and those with a body mass index ≥30 kg/m2 were examined with the extra-large probe. Linear regression models were conducted after adjusting for potential confounding factors of LSMs. We performed several sensitivity analyses. RESULTS We established LSM ranges for healthy individuals measured with both probes-these did not change significantly in sensitivity analyses of individuals with platelets ≥150,000/mm3 and levels of alanine aminotransferase ≤33 IU/L in men or ≤25 IU/L in women. In multivariate analysis, factors that modified LSMs with statistical significance included diabetes, dyslipidemia, waist circumference, level of aspartate aminotransferase, and systolic blood pressure at examination time. Significant increases in LSMs were associated with the metabolic syndrome in individuals examined by either probe. Diabetes in obese individuals increased the risk of LSMs in the range associated with advanced fibrosis. CONCLUSIONS In a systematic review and meta-analysis of data from individual participants, we established a comprehensive set of LSM ranges, measured by TE in large cohorts of healthy individuals and persons susceptible to hepatic fibrosis. Regression analyses identified factors associated with increased LSMs obtained by TE with the medium and extra-large probes.
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Interplay between early-life malnutrition, epigenetic modulation of the immune function and liver diseases.
Campisano, S, La Colla, A, Echarte, SM, Chisari, AN
Nutrition research reviews. 2019;(1):128-145
Abstract
Early-life nutrition plays a critical role in fetal growth and development. Food intake absence and excess are the two main types of energy malnutrition that predispose to the appearance of diseases in adulthood, according to the hypothesis of 'developmental origins of health and disease'. Epidemiological data have shown an association between early-life malnutrition and the metabolic syndrome in later life. Evidence has also demonstrated that nutrition during this period of life can affect the development of the immune system through epigenetic mechanisms. Thus, epigenetics has an essential role in the complex interplay between environmental factors and genetics. Altogether, this leads to the inflammatory response that is commonly seen in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome. In conjunction, DNA methylation, covalent modification of histones and the expression of non-coding RNA are the epigenetic phenomena that affect inflammatory processes in the context of NAFLD. Here, we highlight current understanding of the mechanisms underlying developmental programming of NAFLD linked to epigenetic modulation of the immune system and environmental factors, such as malnutrition.