Intrahepatocellular Lipid Research Articles

Impact of rosuvastatin on metabolic syndrome patients with moderate to severe metabolic associated fatty liver disease without overt diabetes: A randomized clinical trial

ObjectiveThis investigation aimed to evaluate the efficacy and safety of rosuvastatin in treating moderate to severe metabolic associated fatty liver disease (MAFLD). MethodsThis prospective, open-label, randomized study included non-diabetic participants with metabolic syndrome and intrahepatocellular lipid (IHCL) levels >10 %, as determined by proton magnetic resonance spectroscopy (1H-MRS). The primary objective was the effect of a 52-week rosuvastatin treatment (10 mg/day) on IHCL content. Secondary objectives included the association between IHCL reduction and lipid metabolism parameters, along with safety indices such as glycemic control and hepatic and renal function. ResultsThirty-two participants completed the study. Rosuvastatin resulted in a significant absolute (△IHCL: 7.61 ± 4.51 vs. 1.54 ± 5.33, p = 0.002) and relative reduction in IHCL (△IHCL%: −42.28 ± 24.90 % vs. −8.91 ± 31.93 %, p = 0.003) compared to the control. Reduction in IHCL correlated significantly with decreases in low-density lipoprotein cholesterol (LDL-C) (r = 0.574, p < 0.01), apolipoprotein B (ApoB) (r = 0.660, p < 0.001), and free fatty acids (FFA) (r = 0.563, p = 0.005). No significant safety differences were observed between groups. ConclusionsRosuvastatin significantly reduced hepatic steatosis in individuals with moderate to severe MAFLD and metabolic syndrome over 52 weeks, while maintaining a favorable safety profile.

Methodological advancements in organ-specific ectopic lipid quantitative characterization: Effects of high fat diet on muscle and liver intracellular lipids

ObjectiveEctopic lipid accumulation is a hallmark of metabolic diseases, linking obesity to non-alcoholic fatty liver disease, insulin resistance and diabetes. The use of zebrafish as a model of obesity and diabetes is raising due to the conserved properties of fat metabolism between humans and zebrafish, the homologous genes regulating lipid uptake and transport, the implementation of the ‘3R’s principle and their cost-effectiveness. To date, a method allowing the conservation of lipid droplets (LDs) and organs in zebrafish larvae to image ectopic lipids is not available. Our objectives were to develop a novel methodology to quantitatively evaluate organ-specific LDs, in skeletal muscle and liver, in response to a nutritional perturbation. MethodsWe developed a novel embedding and cryosectioning protocol allowing the conservation of LDs and organs in zebrafish larvae. To establish the quantitative measures, we used a three-arm parallel nutritional intervention design. Zebrafish larvae were fed a control diet containing 14% of nutritional fat or two high fat diets (HFDs) containing 25 and 36% of dietary fats. In muscle and liver, LDs were characterized using immunofluorescence confocal microscopy. In liver, intrahepatocellular lipids were discriminated from intrasinusoid lipids. To complete liver characteristics, fibrosis was identified with Masson’s Trichrome staining. Finally, to confirm the conservation and effect of HFD, molecular players of fat metabolism were evaluated by RT-qPCR. ResultsThe cryosections obtained after setting up the embedding and cryopreservation method were of high quality, preserving tissue morphology and allowing the visualization of ectopic lipids. Both HFDs were obesogenic, without modifying larvae survival or development. Neutral lipid content increased with time and augmented dietary fat. Intramuscular LD volume density increased and was explained by an increase in LDs size but not in numbers. Intrahepatocellular LD volume density increased and was explained by an increased number of LDs, not by their increased size. Sinusoid area and lipid content were both increased. Hepatic fibrosis appeared with both HFDs. We observed alterations in the expression of genes associated with LD coating proteins, LD dynamics, lipogenesis, lipolysis and fatty acid oxidation. ConclusionsIn this study, we propose a reproducible and fast method to image zebrafish larvae without losing LD quality and organ morphology. We demonstrate the impact of HFD on LD characteristics in liver and skeletal muscle accompanied by alterations of key players of fat metabolism. Our observations confirm the evolutionarily conserved mechanisms in lipid metabolism and reveal organ specific adaptations. The methodological advancements proposed in this work open the doors to study organelle adaptations in obesity and diabetes related research such as lipotoxicity, organelle contacts and specific lipid depositions.

Andrographolide ameliorates hepatic steatosis by suppressing FATP2-mediated fatty acid uptake in mice with nonalcoholic fatty liver disease

Excessive intrahepatocellular lipid accumulation or steatosis is caused by abnormal lipid metabolism and a common character of nonalcoholic fatty liver disease (NAFLD), which may progress into cirrhosis and hepatocellular cancer. Andrographolide (Andro) is the primary active ingredient extracted from Andrographis paniculata, showing a protective role against dietary steatosis with the mechanism not fully understood. In this study, we showed that administration of Andro (50, 100, and 200 mg/kg/day for 8 weeks, respectively) attenuated obesity and metabolic syndrome in high-fat diet (HFD)-fed mice with improved glucose tolerance, insulin sensitivity, and reduced hyperinsulinemia, hyperglycemia, and hyperlipidemia. HFD-fed mice presented hepatic steatosis, which was significantly prevented by Andro. In vitro, Andro decreased the intracellular lipid droplets in oleic acid-treated LO2 cells. The selected RT-PCR array revealed a robust expression suppression of the fatty acid transport proteins (FATPs) by Andro treatment. Most importantly, we found that Andro consistently reduced the expression of FATP2 in both the oleic acid-treated LO2 cells and liver tissues of HFD-fed mice. Overexpression of FATP2 abolished the lipid-lowering effect of Andro in oleic acid-treated LO2 cells. Andro treatment also reduced the fatty acid uptake in oleic acid-treated LO2 cells, which was blunted by FATP2 overexpression. Collectively, our findings reveal a novel mechanism underlying the anti-steatosis effect of Andro by suppressing FATP2-mediated fatty acid uptake, suggesting the potential therapeutic application of Andro in the treatment of NAFLD.Graphical abstract

Important Food Sources of Fructose-Containing Sugars and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Controlled Trials.

Background: Fructose providing excess calories in the form of sugar sweetened beverages (SSBs) increases markers of non-alcoholic fatty liver disease (NAFLD). Whether this effect holds for other important food sources of fructose-containing sugars is unclear. To investigate the role of food source and energy, we conducted a systematic review and meta-analysis of controlled trials of the effect of fructose-containing sugars by food source at different levels of energy control on non-alcoholic fatty liver disease (NAFLD) markers. Methods and Findings: MEDLINE, Embase, and the Cochrane Library were searched through 7 January 2022 for controlled trials ≥7-days. Four trial designs were prespecified: substitution (energy-matched substitution of sugars for other macronutrients); addition (excess energy from sugars added to diets); subtraction (excess energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced by other macronutrients). The primary outcome was intrahepatocellular lipid (IHCL). Secondary outcomes were alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Independent reviewers extracted data and assessed risk of bias. The certainty of evidence was assessed using GRADE. We included 51 trials (75 trial comparisons, n = 2059) of 10 food sources (sugar-sweetened beverages (SSBs); sweetened dairy alternative; 100% fruit juice; fruit; dried fruit; mixed fruit sources; sweets and desserts; added nutritive sweetener; honey; and mixed sources (with SSBs)) in predominantly healthy mixed weight or overweight/obese younger adults. Total fructose-containing sugars increased IHCL (standardized mean difference = 1.72 [95% CI, 1.08 to 2.36], p < 0.001) in addition trials and decreased AST in subtraction trials with no effect on any outcome in substitution or ad libitum trials. There was evidence of influence by food source with SSBs increasing IHCL and ALT in addition trials and mixed sources (with SSBs) decreasing AST in subtraction trials. The certainty of evidence was high for the effect on IHCL and moderate for the effect on ALT for SSBs in addition trials, low for the effect on AST for the removal of energy from mixed sources (with SSBs) in subtraction trials, and generally low to moderate for all other comparisons. Conclusions: Energy control and food source appear to mediate the effect of fructose-containing sugars on NAFLD markers. The evidence provides a good indication that the addition of excess energy from SSBs leads to large increases in liver fat and small important increases in ALT while there is less of an indication that the removal of energy from mixed sources (with SSBs) leads to moderate reductions in AST. Varying uncertainty remains for the lack of effect of other important food sources of fructose-containing sugars at different levels of energy control.

GCKIII kinases in lipotoxicity: Roles in NAFLD and beyond.

Nonalcoholic fatty liver disease (NAFLD) is defined by excessive accumulation of lipid droplets within hepatocytes. The STE20‐type kinases comprising the germinal center kinase III (GCKIII) subfamily – MST3, MST4, and STK25 – decorate intrahepatocellular lipid droplets and have recently emerged as critical regulators of the initiation and progression of NAFLD. While significant advancement has been made toward deciphering the role of GCKIII kinases in hepatic fat accumulation (i.e., steatosis) as well as the aggravation of NAFLD into its severe form nonalcoholic steatohepatitis (NASH), much remains to be resolved. This review provides a brief overview of the recent studies in patient cohorts, cultured human cells, and mouse models, which have characterized the function of MST3, MST4, and STK25 in the regulation of hepatic lipid accretion, meta‐inflammation, and associated cell damage in the context of NAFLD/NASH. We also highlight the conflicting data and emphasize future research directions that are needed to advance our understanding of GCKIII kinases as potential targets in the therapy of NAFLD and its comorbidities. Conclusions: Several lines of evidence suggest that GCKIII proteins govern the susceptibility to hepatic lipotoxicity and that pharmacological inhibition of these kinases could mitigate NAFLD development and aggravation. Comprehensive characterization of the molecular mode‐of‐action of MST3, MST4, and STK25 in hepatocytes as well as extrahepatic tissues is important, especially in relation to their impact on carcinogenesis, to fully understand the efficacy as well as safety of GCKIII antagonism.

Corydalis saxicola Bunting Total Alkaloids ameliorate diet-induced non-alcoholic steatohepatitis by regulating hepatic PI3K/Akt and TLR4/NF-κB pathways in mice

Corydalis saxicola Bunting (Yanhuanglian), distributed in Southwest China, is mainly used for treatment of hepatitis, oral mucosal erosion, conjunctivitis, dysentery, acute abdominal pain and hemorrhoids in the folk. Corydalis saxicola Bunting Total Alkaloids (CSBTA) are the active ingredients extracted from the root of C. saxicola bunting. Non-alcoholic steatohepatitis (NASH) is the hinge between steatosis and cirrhosis in the spectrum of Non-alcoholic fatty liver disease (NAFLD), which has become one of the most common chronic liver diseases in the world. CSBTA can reduce tumors and brain diseases through anti-inflammatory and antioxidant pathways. Our study was designed to clarify the effects of CSBTA on the HFHC (High fat and high carbohydrate drinking) diet induced mice. In our research, A HFHC diet induced NASH mice model was applied to investigate the effects of CSBTA in vivo and obeticholic acid (OA) was set as positive control. Moreover, the underlying mechanisms were explored by palmitic acid (PA) and lipopolysaccharide (LPS) stimulated HepG2 cells in vitro. The in vivo study illustrated that CSBTA could alleviate mice away from the onset of NASH, and reduce intrahepatocellular lipid accumulation and hepatocyte inflammation under high fat condition. Further in vitro analysis confirmed that CSBTA attenuated inflammation and hepatic lipid accumulation by improving hepatic PI3K/Akt and suppressing hepatic TLR4/NF-κB pathways. In summary, this study demonstrated that CSBTA might be a promising compound for the treatment of NAFLD.

Association of Low- and No-Calorie Sweetened Beverages as a Replacement for Sugar-Sweetened Beverages With Body Weight and Cardiometabolic Risk

There are concerns that low- and no-calorie sweetened beverages (LNCSBs) do not have established benefits, with major dietary guidelines recommending the use of water and not LNCSBs to replace sugar-sweetened beverages (SSBs). Whether LNCSB as a substitute can yield similar improvements in cardiometabolic risk factors vs water in their intended substitution for SSBs is unclear. To assess the association of LNCSBs (using 3 prespecified substitutions of LNCSBs for SSBs, water for SSBs, and LNCSBs for water) with body weight and cardiometabolic risk factors in adults with and without diabetes. Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception through December 26, 2021. Randomized clinical trials (RCTs) with at least 2 weeks of interventions comparing LNCSBs, SSBs, and/or water were included. Data were extracted and risk of bias was assessed by 2 independent reviewers. A network meta-analysis was performed with data expressed as mean difference (MD) or standardized mean difference (SMD) with 95% CIs. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to assess the certainty of the evidence. The primary outcome was body weight. Secondary outcomes were other measures of adiposity, glycemic control, blood lipids, blood pressure, measures of nonalcoholic fatty liver disease, and uric acid. A total of 17 RCTs with 24 trial comparisons were included, involving 1733 adults (mean [SD] age, 33.1 [6.6] years; 1341 women [77.4%]) with overweight or obesity who were at risk for or had diabetes. Overall, LNCSBs were a substitute for SSBs in 12 RCTs (n = 601 participants), water was a substitute for SSBs in 3 RCTs (n = 429), and LNCSBs were a substitute for water in 9 RCTs (n = 974). Substitution of LNCSBs for SSBs was associated with reduced body weight (MD, -1.06 kg; 95% CI, -1.71 to -0.41 kg), body mass index (MD, -0.32; 95% CI, -0.58 to -0.07), percentage of body fat (MD, -0.60%; 95% CI, -1.03% to -0.18%), and intrahepatocellular lipid (SMD, -0.42; 95% CI, -0.70 to -0.14). Substituting water for SSBs was not associated with any outcome. There was also no association found between substituting LNCSBs for water with any outcome except glycated hemoglobin A1c (MD, 0.21%; 95% CI, 0.02% to 0.40%) and systolic blood pressure (MD, -2.63 mm Hg; 95% CI, -4.71 to -0.55 mm Hg). The certainty of the evidence was moderate (substitution of LNCSBs for SSBs) and low (substitutions of water for SSBs and LNCSBs for water) for body weight and was generally moderate for all other outcomes across all substitutions. This systematic review and meta-analysis found that using LNCSBs as an intended substitute for SSBs was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm and had a similar direction of benefit as water substitution. The evidence supports the use of LNCSBs as an alternative replacement strategy for SSBs over the moderate term in adults with overweight or obesity who are at risk for or have diabetes.

Advanced Molecular Imaging (MRI/MRS/1H NMR) for Metabolic Information in Young Adults with Health Risk Obesity.

Background: Obesity or being overweight is a medical condition of abnormal body fat accumulation which is associated with a higher risk of developing metabolic syndrome. The distinct body fat depots on specific parts of the anatomy have unique metabolic properties and different types of regional excessive fat distribution can be a disease hazard. The aim of this study was to identify the metabolome and molecular imaging phenotypes among a young adult population. Methods: The amount and distribution of fat and lipid metabolites profile in the abdomen, liver, and calf muscles of 46 normal weight, 17 overweight, and 13 obese participants were acquired using MRI and MR spectroscopy (MRS), respectively. The serum metabolic profile was obtained using proton NMR spectroscopy. NMR spectra were integrated into seven integration regions, which reflect relative metabolites. Results: A significant metabolic disorder symptom appeared in the overweight and obese group, and increased lipid deposition occurred in the abdomen, hepatocytes, and muscles that were statistically significant. Overall, the visceral fat depots had a marked influence on dyslipidemia biomarkers, blood triglyceride (r = 0.592, p < 0.001), and high-density lipoprotein cholesterol (r = −0.484, p < 0.001). Intrahepatocellular lipid was associated with diabetes predictors for hemoglobin (HbA1c%; r = 0.379, p < 0.001) and for fasting blood sugar (r = 0.333, p < 0.05). The lipid signals in serum triglyceride and glucose signals gave similar correspondence to biochemical lipid profiles. Conclusions: This study proves the association between alteration in metabolome in young adults, which is the key population for early prevention of obesity and metabolic syndrome. This study suggests that dyslipidemia prevalence is influenced mainly by the visceral fat depot, and liver fat depot is a key determinant for glucose metabolism and hyperglycemia. Moreover, noninvasive advanced molecular imaging completely elucidated the impact of fat distribution on the anthropometric and laboratory parameters, especially indices of the metabolic syndrome biomarkers in young adults.

Insulin resistance and NAFLD may influence memory performance in obese patients with prediabetes or newly-diagnosed type 2 diabetes

Background and aimsDiabetes has consistently been shown to increase risk for cognitive decline. Cognitive deficits may occur at the very earliest stages of diabetes.We sought to estimate the determinants of memory function in a group of middle-aged obese subjects with prediabetes or newly-diagnosed type 2 diabetes mellitus. Methods and resultsSixty-two obese patients in treatment with metformin-with prediabetes (n = 41) or newly diagnosed T2DM (n = 21), were studied. Short- and long-term memory function was assessed through a neuropsychological assessment consisting of two tests and a composite domain z score was calculated. Cardiometabolic variables, such as abdominal MRI quantification of subcutaneous (SAT) and visceral (VAT) adipose tissue content, and of intra-hepatocellular lipid content, as well as insulin sensitivity (Matsuda Index, HOMA-IR) and beta cell performance (Beta Index), by multiple sampling, 8-point oral glucose tolerance test, were also evaluated.Age, non-alcoholic fatty liver disease (NAFLD), and lnHOMA-IR together explained 18% (R square) of the variance in memory domain. Including NAFLD increased the explained variance by 8% and including lnHOMA-IR by 9.1%, whereas the contribution of age and other factors was negligible. ConclusionPreventing and managing insulin resistance in precocious and possibly earlier stages of diabetes might provide benefit in slowering down future cognitive decline.

Effect of Important Food Sources of Fructose-Containing Sugars on Non-alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Controlled Trials

ObjectivesFructose as a source of excess calories increases non-alcoholic fatty liver disease (NAFLD) markers. Whether this effect is mediated by the food matrix is unknown. We thus conducted a systematic review and meta-analysis of controlled feeding trials assessing the effect of important food sources of fructose-containing sugars at different energy control levels on NAFLD markers. MethodsMEDLINE, Embase, and Cochrane Library were searched through January 18, 2021 for controlled trials ≥7-days. Four trial designs were prespecified based on energy control: substitution (energy-matched replacement of sugars by other macronutrients); addition (excess energy from sugars added to diets); subtraction (energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced by other macronutrients). The primary outcome was intrahepatocellular lipid (IHCL). Secondary outcomes were alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Independent reviewers extracted data and assessed risk of bias. Certainty of evidence was assessed by GRADE. ResultsWe included 44 trials (65 trial comparisons, n = 1941) assessing the effect of 8 food sources (sugar-sweetened beverages [SSBs]; sweetened dairy alternative [soy]; fruit juice; fruit; dried fruit; baked goods, desserts and sweets; added nutritive sweetener; and mixed sources) across 4 energy levels. Total fructose-containing sugars increased IHCL in addition trials (standardized mean difference = 1.69 [95% CI, 1.00–2.37], P < 0.001), but no effect in substitution, subtraction and ad libitum trials. There was evidence of interaction by food source in addition trials with SSBs increasing IHCL and ALT, and mixed sources increasing AST. The overall certainty of evidence was high for SSBs on IHCL and ALT in addition trials and high to very low for all other comparisons. ConclusionsEnergy control and food source appear to mediate the effect of fructose-containing sugars on NAFLD markers. High certainty evidence suggests that SSBs providing excess energy increase NAFLD markers, while the evidence is less certain that mixed sources share the same effect and other food sources do not. More high-quality randomized trials of different food sources are needed to improve our estimates (ClinicalTrials.gov identifier, NCT02716870). Funding SourcesPrimary funding: Diabetes Canada.

Lipid droplet-associated kinase STK25 regulates peroxisomal activity and metabolic stress response in steatotic liver

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide and have been recognized as one of the major unmet medical needs of the 21st century. Our recent translational studies in mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine kinase (STK)25 as a protein that coats intrahepatocellular lipid droplets (LDs) and critically regulates liver lipid homeostasis and progression of NAFLD/NASH. Here, we studied the mechanism-of-action of STK25 in steatotic liver by relative quantification of the hepatic LD-associated phosphoproteome from high-fat diet-fed Stk25 knockout mice compared with their wild-type littermates. We observed a total of 131 proteins and 60 phosphoproteins that were differentially represented in STK25-deficient livers. Most notably, a number of proteins involved in peroxisomal function, ubiquitination-mediated proteolysis, and antioxidant defense were coordinately regulated in Stk25-/- versus wild-type livers. We confirmed attenuated peroxisomal biogenesis and protection against oxidative and ER stress in STK25-deficient human liver cells, demonstrating the hepatocyte-autonomous manner of STK25's action. In summary, our results suggest that regulation of peroxisomal function and metabolic stress response may be important molecular mechanisms by which STK25 controls the development and progression of NAFLD/NASH.

Lipid emulsions for parenterally fed preterm infants.

Lipid emulsions for parenterally fed preterm infants.

Effects of Dietary Protein and Fat Content on Intrahepatocellular and Intramyocellular Lipids during a 6-Day Hypercaloric, High Sucrose Diet: A Randomized Controlled Trial in Normal Weight Healthy Subjects.

Sucrose overfeeding increases intrahepatocellular (IHCL) and intramyocellular (IMCL) lipid concentrations in healthy subjects. We hypothesized that these effects would be modulated by diet protein/fat content. Twelve healthy men and women were studied on two occasions in a randomized, cross-over trial. On each occasion, they received a 3-day 12% protein weight maintenance diet (WM) followed by a 6-day hypercaloric high sucrose diet (150% energy requirements). On one occasion the hypercaloric diet contained 5% protein and 25% fat (low protein-high fat, LP-HF), on the other occasion it contained 20% protein and 10% fat (high protein-low fat, HP-LF). IHCL and IMCL concentrations (magnetic resonance spectroscopy) and energy expenditure (indirect calorimetry) were measured after WM, and again after HP-LF/LP-HF. IHCL increased from 25.0 ± 3.6 after WM to 147.1 ± 26.9 mmol/kg wet weight (ww) after LP-HF and from 30.3 ± 7.7 to 57.8 ± 14.8 after HP-LF (two-way ANOVA with interaction: p < 0.001 overfeeding x protein/fat content). IMCL increased from 7.1 ± 0.6 to 8.8 ± 0.7 mmol/kg ww after LP-HF and from 6.2 ± 0.6 to 6.9 ± 0.6 after HP-LF, (p < 0.002). These results indicate that liver and muscle fat deposition is enhanced when sucrose overfeeding is associated with a low protein, high fat diet compared to a high protein, low fat diet.

Impact of sleep restriction on metabolic outcomes induced by overfeeding: a randomized controlled trial in healthy individuals

Overconsumption of energy-dense foods and sleep restriction are both associated with the development of metabolic and cardiovascular diseases, but their combined effects remain poorly evaluated. The aim of this study was to assess whether sleep restriction potentiates the effects of a short-term overfeeding on intrahepatocellular lipid (IHCL) concentrations and on glucose homeostasis. Ten healthy subjects were exposed to a 6-d overfeeding period (130% daily energy needs, with 15% extra energy as sucrose and 15% as fat), with normal sleep (8 h sleep opportunity time) or sleep restriction (4 h sleep opportunity time), according to a randomized, crossover design. At baseline and after intervention, IHCL concentrations were measured by proton magnetic resonance spectroscopy, and a dual intravenous [6,6-2H2]-, oral 13C-labeled glucose tolerance test and a polysomnographic recording wereperformed. Overfeeding significantly increased IHCL concentrations (Poverfeeding<0.001; overfeeding+normal sleep: +53%±16%). During the oral glucose tolerance test, overfeeding significantly increased endogenous glucose production (Poverfeeding=0.034) and the oxidation of 13C-labeled glucose load (Poverfeeding=0.038). Sleep restriction significantly decreased total sleep time, and the duration of stages 1 and 2 and rapid eye movement sleep (all P<0.001), whereas slow-wave sleep duration was preserved (Poverfeeding × sleep=0.809). Compared with overfeeding, overfeeding+sleep restriction did not change IHCL concentrations (Poverfeeding × sleep=0.541; +83%±33%), endogenous glucose production (Poverfeeding × sleep=0.567), or exogenous glucose oxidation (Poverfeeding × sleep=0.118). Sleep restriction did not significantly alter blood pressure, heart rate, or plasma cortisol concentrations (all Poverfeeding × sleep=NS). Six days of a high-sucrose, high-fat overfeeding diet significantly increased IHCL concentrations and increased endogenous glucose production, suggesting hepatic insulin resistance. These effects of overfeeding were not altered by sleep restriction. This trial was registered at clinicaltrials.gov as NCT02075723. Other study ID numbers: SleepDep 02/14.

The effects of dietary supplementation with inulin and inulin-propionate ester on hepatic steatosis in adults with non-alcoholic fatty liver disease.

The short chain fatty acid (SCFA) propionate, produced through fermentation of dietary fibre by the gut microbiota, has been shown to alter hepatic metabolic processes that reduce lipid storage. We aimed to investigate the impact of raising colonic propionate production on hepatic steatosis in adults with non‐alcoholic fatty liver disease (NAFLD). Eighteen adults were randomized to receive 20 g/d of an inulin‐propionate ester (IPE), designed to deliver propionate to the colon, or an inulin control for 42 days in a parallel design. The change in intrahepatocellular lipid (IHCL) following the supplementation period was not different between the groups (P = 0.082), however, IHCL significantly increased within the inulin‐control group (20.9% ± 2.9% to 26.8% ± 3.9%; P = 0.012; n = 9), which was not observed within the IPE group (22.6% ± 6.9% to 23.5% ± 6.8%; P = 0.635; n = 9). The predominant SCFA from colonic fermentation of inulin is acetate, which, in a background of NAFLD and a hepatic metabolic profile that promotes fat accretion, may provide surplus lipogenic substrate to the liver. The increased colonic delivery of propionate from IPE appears to attenuate this acetate‐mediated increase in IHCL.

Impaired repletion of intramyocellular lipids in patients with growth hormone deficiency after a bout of aerobic exercise

BackgroundEctopic lipids such as intramyocellular lipids (IMCL) are depleted by exercise and repleted by diet, whereas intrahepatocellular lipids (IHCL) are increased immediately after exercise. So far, it is unclear how ectopic lipids behave 24 h after exercise and whether the lack of growth hormone (GH) significantly affects ectopic lipids 24 h after exercise. MethodsSeven male patients with growth hormone deficiency (GHD) and seven sedentary male control subjects (CS) were included. VO2max was assessed by spiroergometry; visceral and subcutaneous fat by whole body MRI. 1H-MR-spectroscopy was performed in M. vastus intermedius and in the liver before and after 2 h of exercise at 50% VO2max and 24 h thereafter, while diet and physical activity were standardized. ResultsSedentary male subjects (7 GHD, 7 CS) were recruited. Age, BMI, waist circumference, visceral and subcutaneous fat mass was not significantly different between GHD and CS. VO2max was significantly lower in GHD vs. CS. IMCL were diminished through aerobic exercise in both groups: (−11.5 ± 21.9% in CS; −8.9% ±19.1% in GHD) and restored after 24 h in CS (−5.5 ± 26.6% compared to baseline) but not in GHD (−17.9 ± 15.3%). IHCL increased immediately after exercise and decreased to baseline within 24 h. ConclusionThese findings suggest that GHD may affect repletion of IMCL 24 h after aerobic exercise.

Is non-alcoholic fatty liver disease a reflection of what we eat or simply how much we eat?

Non‐alcoholic fatty liver disease (NAFLD) is an increasingly common and potentially serious condition, which has emerged with the obesity epidemic. This disease can progress to cirrhosis and hepatocellular cancer. Associated comorbidities, such as cardiovascular disease and type 2 diabetes, are common. Obesity is the key risk factor and diet appears to be a critical factor in the pathogenesis of NAFLD. We reviewed studies undertaken on human subjects investigating which dietary components initiate excess hepatic triglyceride deposition. Most experimental diets used high‐calorie excesses, or extreme proportions of fat or carbohydrate, not typical of current dietary patterns. Hypercaloric diets, where the additional calories were predominantly either fat or carbohydrates, increased intrahepatocellular lipids. The type of fat appeared important, with diets high in saturated fatty acids favoring hepatic fat accumulation which was substantially lower with polyunsaturated fatty acids. The effect of dietary fructose on markers of NAFLD did not appear to be worse than that of glucose. The initiation of excess hepatic triglycerides is likely to be a complex interaction of energy and nutrients with more than one dietary factor involved. It was not possible to disentangle the hepatic effects of excess energy from that of different macronutrient distributions in current literature. Further investigation is needed to determine the type of diet that is likely to lead to the development of NAFLD. A better understanding of the contribution of diet to pathogenesis of NAFLD would better inform prevention strategies.

Body Composition following Necrotising Enterocolitis in Preterm Infants

Background: The optimal nutritional regimen for preterm infants, including those that develop necrotising enterocolitis (NEC), is unknown. Objective: The objective here was to evaluate body composition at term in infants following NEC, in comparison with healthy infants. The primary outcome measure was non-adipose tissue mass (non-ATM). Methods: We compared body composition assessed by magnetic resonance imaging at term in infants born <31 weeks of gestational age that participated in NEON, a trial comparing incremental versus immediate delivery of parenteral amino acids on non-ATM, and SMOF versus intralipid on intrahepatocellular lipid content. There were no differences in the primary outcomes. We compared infants that received surgery for NEC (NEC-surgical), infants with medically managed NEC (NEC-medical), and infants without NEC (reference). Results: A total of 133 infants were included (8 NEC-surgical; 15 NEC-medical; 110 reference). In comparison with the reference group, infants in the NEC-surgical and NEC-medical groups were significantly lighter [adjusted mean difference (95% CI) NEC-surgical: –630 g (–1,010, –210), p = 0.003; NEC-medical: –440 g (–760, –110), p = 0.009] and the total adipose tissue volume (ATV) was significantly lower [NEC-surgical: –360 cm³ (–516, –204), p < 0.001; NEC-medical: –127 cm³ (–251, –4); p = 0.043]. There were no significant differences in non-ATM [adjusted mean difference (95% CI) NEC-surgical: –46 g (–281, 189), p = 0.70; NEC-medical: –122 g (–308, 63), p = 0.20]. Conclusion: The lower weight at term in preterm infants following surgically and medically managed NEC, in comparison to preterm infants that did not develop the disease, was secondary to a reduction in ATV. This suggests that the nutritional regimen received was adequate to preserve non-ATM but not to support the normal third-trimester deposition of adipose tissue in preterm infants.

Metabolic Effects of Replacing Sugar-Sweetened Beverages with Artificially-Sweetened Beverages in Overweight Subjects with or without Hepatic Steatosis: A Randomized Control Clinical Trial.

Objective: Addition of fructose to the diet of normal weight and overweight subjects can increase postprandial plasma triglyceride and uric acid concentration. We, therefore, assessed whether replacing sugar-sweetened beverages (SSB) with artificially-sweetened beverages (ASB) in the diet of overweight and obese subjects would decrease these parameters. Methods: Twenty-six participants of the REDUCS study, which assessed the effects of replacing SSB by ASB over 12 weeks on intra-hepatocellular lipid concentration, were included in this sub-analysis. All were studied after a four-week run-in period during which they consumed their usual diet and SSBs, and after a 12-week intervention in which they were randomly assigned to replace their SSBs with ASBs (ASB arm) or to continue their usual diet and SSBs (control arm, CTRL). At the end of run-in (week 4) and again at the end of intervention (week 16), they took part in an 8.5 h metabolic investigation during which their plasma glucose, insulin, glucagon, lactate, triglyceride (TG), non-esterified fatty acids (NEFA), and uric acid concentrations were measured over a 30 min fasting period (−30–0 min), then every 2 h over 480 min. with ingestion of standard breakfast at time 0 min and a standard lunch at time 240 min. Breakfast and lunch were consumed together with a 3.3 dL SSB at week 4 and with either an ASB (ASB arm) or a SSB (CTRL arm) at week 16. After analyzing the whole group, a secondary analysis was performed on 14 subjects with hepatic steatosis (seven randomized to ASB, seven to CTRL) and 12 subjects without hepatic steatosis (six randomized to ASB and six to CTRL). Results: Ingestion of meals increased plasma glucose, insulin, glucagon, lactate, and TG concentrations and decreased NEFA concentrations, but with no significant difference of integrated postprandial responses between week 4 and week 16 in both ASB and CTRL, except for a slightly decreased glucagon response in ASB. There was, however, no significant postprandial increase in uric acid concentration in both arms. In the secondary analysis, replacing SSBs with ASBs did not significantly change postprandial TG and uric acid concentrations irrespective of the presence or not of hepatic steatosis, Conclusions: In overweight, high SSB consumers, replacing SSBs with ASBs during 12 weeks did not significantly alter post-prandial TG and uric acid concentration, in spite of the lower energy and fructose content of the meals. These effects were globally the same in subjects without and with hepatic steatosis.

The Flexibility of Ectopic Lipids.

In addition to the subcutaneous and the visceral fat tissue, lipids can also be stored in non-adipose tissue such as in hepatocytes (intrahepatocellular lipids; IHCL), skeletal (intramyocellular lipids; IMCL) or cardiac muscle cells (intracardiomyocellular lipids; ICCL). Ectopic lipids are flexible fuel stores that can be depleted by physical exercise and repleted by diet. They are related to obesity and insulin resistance. Quantification of IMCL was initially performed invasively, using muscle biopsies with biochemical and/or histological analysis. 1H-magnetic resonance spectroscopy (1H-MRS) is now a validated method that allows for not only quantifying IMCL non-invasively and repeatedly, but also assessing IHCL and ICCL. This review summarizes the current available knowledge on the flexibility of ectopic lipids. The available evidence suggests a complex interplay between quantitative and qualitative diet, fat availability (fat mass), insulin action, and physical exercise, all important factors that influence the flexibility of ectopic lipids. Furthermore, the time frame of the intervention on these parameters (short-term vs. long-term) appears to be critical. Consequently, standardization of physical activity and diet are critical when assessing ectopic lipids in predefined clinical situations.