Greater hepatic lipid saturation is associated with impaired glycaemic regulation in men with metabolic dysfunction-associated steatotic liver disease but is not altered by 6 weeks of exercise training.

AIMS: To examine the impact of impaired glycaemic regulation (IGR) and exercise training on hepatic lipid composition in men with metabolic dysfunction-associated steatotic liver disease (MASLD). MATERIALS AND METHODS: In Part A (cross-sectional design), 40 men with MASLD (liver proton density fat fraction [PDFF] ≥5.56%) were recruited to one of two groups: (1) normal glycaemic regulation (NGR) group (glycated haemoglobin [HbA1c] < 42 mmol∙mol-1 [<6.0%]; n = 14) or (2) IGR group (HbA1c ≥ 42 mmol∙mol-1 [≥6.0%]; n = 26). In Part B (randomized controlled trial design), participants in the IGR group were randomized to one of two 6-week interventions: (1) exercise training (EX; 70%-75% maximum heart rate; four sessions/week; n = 13) or (2) non-exercise control (CON; n = 13). Saturated (SI; primary outcome), unsaturated (UI) and polyunsaturated (PUI) hepatic lipid indices were determined using proton magnetic resonance spectroscopy. Additional secondary outcomes included liver PDFF, HbA1c, fasting plasma glucose (FPG), homeostatic model assessment of insulin resistance (HOMA-IR), peak oxygen uptake (VO2 peak), and plasma cytokeratin-18 (CK18) M65, among others. RESULTS: In Part A, hepatic SI was higher and hepatic UI was lower in the IGR versus the NGR group (p = 0.038), and this hepatic lipid profile was associated with higher HbA1c levels, FPG levels, HOMA-IR and plasma CK18 M65 levels (rs ≥0.320). In Part B, hepatic lipid composition and liver PDFF were unchanged after EX versus CON (p ≥ 0.257), while FPG was reduced and VO2 peak was increased (p ≤ 0.030). ΔVO2 peak was inversely associated with Δhepatic SI (r = -0.433) and positively associated with Δhepatic UI and Δhepatic PUI (r ≥ 0.433). CONCLUSIONS: Impaired glycaemic regulation in MASLD is characterized by greater hepatic lipid saturation; however, this composition is not altered by 6 weeks of moderate-intensity exercise training.

The role of hepatic lipid composition in obesity-related metabolic disease.

Obesity is a primary antecedent to non-alcoholic fatty liver disease whose cardinal feature is excessive hepatic lipid accumulation. Although total hepatic lipid content closely associates with hepatic and systemic metabolic dysfunction, accumulating evidence suggests that the composition of hepatic lipids may be more discriminatory. This review summarises cross-sectional human studies using liver biopsy/lipidomics and proton magnetic resonance spectroscopy to characterise hepatic lipid composition in people with obesity and related metabolic disease. A comprehensive literature search identified 26 relevant studies published up to 31st March 2021 which were included in the review. The available evidence provides a consistent picture showing that people with hepatic steatosis possess elevated saturated and/or monounsaturated hepatic lipids and a reduced proportion of polyunsaturated hepatic lipids. This altered hepatic lipid profile associates more directly with metabolic derangements, such as insulin resistance, and may be exacerbated in non-alcoholic steatohepatitis. Further evidence from lipidomic studies suggests that these deleterious changes may be related to defects in lipid desaturation and elongation, and an augmentation of the de novo lipogenic pathway. These observations are consistent with mechanistic studies implicating saturated fatty acids and associated bioactive lipid intermediates (ceramides, lysophosphatidylcholines and diacylglycerol) in the development of hepatic lipotoxicity and wider metabolic dysfunction, whilst monounsaturated fatty acids and polyunsaturated fatty acids may exhibit a protective role. Future studies are needed to prospectively determine the relevance of hepatic lipid composition for hepatic and non-hepatic morbidity and mortality; and to further evaluate the impact of therapeutic interventions such as pharmacotherapy and lifestyle interventions.

Current and Future Magnetic Resonance Technologies for Assessing Liver Disease in Clinical and Experimental Medicine.

BACKGROUND: In the past decades, a number of non-invasive methods have emerged for detecting and estimating liver fibrosis; these include both serum-based panels and imaging-based technology. Some of these methods are now being incorporated in clinical practice. However, the limitations of the current techniques include lack of organ specificity, sampling errors and limited ability to reflect the efficacy of interventions. Key Messages: Novel magnetic resonance (MR)-based techniques provide an opportunity to bring about further changes in the investigations and management of patients with liver diseases. Multimodal quantitative MR techniques enable the estimation of fat, iron accumulation, degree of liver injury/inflammation and fibrosis within the whole liver without the need for administering contrast agents. Architectural changes within the liver can be evaluated concurrently with portal haemodynamic changes allowing non-invasive assessment of portal hypertension and effects of interventions. A combination ultra-high field (7T) provides greater sensitivity with a potential to distinguish inflammation from fibrosis on imaging and determine specific types of fats (saturated vs. unsaturated) present within the liver using MR spectroscopy. 13C MR spectroscopy can estimate glutathione flux and rate of beta oxidation in-vivo providing novel tools for experimental studies that evaluate the efficacy of interventions as well as underlying mechanisms. CONCLUSIONS: Translational research should focus on converting the potentials of these innovative methodologies into clinical applications for the benefit of patients.

Liver glycogen stores via 13C magnetic resonance spectroscopy in healthy children: randomized, controlled study.

BACKGROUND: Owing to its role in glucose homeostasis, liver glycogen concentration ([LGly]) can be a marker of altered metabolism seen in disorders that impact the health of children. However, there is a paucity of normative data for this measure in children to allow comparison with patients, and time-course assessment of [LGly] in response to feeding has not been reported. In addition, carbon-13 magnetic resonance spectroscopy (13C-MRS) is used extensively in research to assess liver metabolites in adult health and disease noninvasively, but similar measurements in children are lacking. OBJECTIVES: The main objectives were to quantify the depletion of [LGly] after overnight fasting and the subsequent response to feeding. METHODS: In a randomly assigned, open-label, incomplete block design study, healthy, normal-weight children (8-12 y) attended 2 evening visits, each separated by ≥5 d and directly followed by a morning visit. An individually tailored, standardized meal was consumed 3-h prior to evening assessments. Participants then remained fasted until the morning visit. [LGly] was assessed once in the fed (20:00) and fasted state (08:00) using 13C-MRS. After the 8:00 assessment, 200 ml of a mixed-macronutrient drink containing 15.5 g (402 kJ) or 31 g carbohydrates (804 kJ), or water only, was consumed, with 13C-MRS measurements then performed hourly for 4 h. Each child was randomly assigned to 2 of 3 drink options across the 2 mornings. Data are expressed as mean (SD). RESULTS: Twenty-four children including females and males (13F:11M) completed the study [9.9 (1.1) y, BMI percentile 45.7 (25.9)]. [LGly] decreased from 377.9 (141.3) to 277.3 (107.4) mmol/L overnight; depletion rate 0.14 (0.15) mmol/L min. Incremental responses of [LGly] to test drinks differed (P < 0.001), with incremental net area under the curve of [LGly] over 4 h being higher for 15.5 g [-67.1 (205.8) mmol/L·240 min; P < 0.01] and 31 g carbohydrates [101.6 (180.9) mmol/L·240 min; P < 0.005] compared with water [-253.1 (231.2) mmol/L·240 min]. CONCLUSIONS: After overnight fasting, [LGly] decreased by 22.9 (25.1)%, and [LGly] incremental net area under the curve over 4 h was higher after subsequent consumption of 15.5 g and 31 g carbohydrates, compared to water. Am J Clin Nutr 20XX;xx:xx-xx.

Metabolic Imaging in Non-Alcoholic Fatty Liver Disease: Applications of Magnetic Resonance Spectroscopy.

Non-alcoholic fatty liver disease (NAFLD) is poised to dominate the landscape of clinical hepatology in the 21st century. Its complex, interdependent aetiologies, non-linear disease progression and uncertain natural history have presented great challenges to the development of effective therapies. Progress will require an integrated approach to uncover molecular mediators, key pathogenic milestones and response to intervention at the metabolic level. The advent of precision imaging has yielded unprecedented insights into these processes. Quantitative imaging biomarkers such as magnetic resonance imaging (MRI), spectroscopy (MRS) and elastography (MRE) present robust, powerful tools with which to probe NAFLD metabolism and fibrogenesis non-invasively, in real time. Specific advantages of MRS include the ability to quantify static metabolite concentrations as well as dynamic substrate flux in vivo. Thus, a vast range of key metabolic events in the natural history of NAFLD can be explored using MRS. Here, we provide an overview of MRS for the clinician, as well as key pathways exploitable by MRS in vivo. Development, optimisation and validation of multinuclear MRS, in combination with other quantitative imaging techniques, may ultimately provide a robust, non-invasive alternative to liver biopsy for observational and longitudinal studies. Through enabling deeper insight into inflammatory and fibrogenic cascades, MRS may facilitate identification of novel therapeutic targets and clinically meaningful endpoints in NAFLD. Its widespread use in future could conceivably accelerate study design, data acquisition and availability of disease-modifying therapies at a population level.

Corticotropin-releasing factor increases ascending colon volume after a fructose test meal in healthy humans: a randomized controlled trial.

BACKGROUND: Poorly absorbed fermentable carbohydrates can provoke irritable bowel syndrome (IBS) symptoms by escaping absorption in the small bowel and being rapidly fermented in the colon in some susceptible subjects. IBS patients often are anxious and stressed, and stress accelerates small bowel transit, which may exacerbate malabsorption. OBJECTIVE: In this study we investigated the effect of an intravenous injection of corticotropin-releasing factor (CRF) on fructose malabsorption and the resulting volume of water in the small bowel. DESIGN: We performed a randomized, placebo-controlled crossover study of CRF compared with saline injection in 11 male and 10 female healthy subjects, examining the effect on the malabsorption of a 40-g fructose test meal and its transit through the gut, which was assessed by serial MRI and breath hydrogen measurement. Orocecal transit was assessed with the use of the lactose [(13)C]ureide breath test and the adrenal response to CRF was assessed by serial salivary cortisol measurements. RESULTS: CRF injection caused a significant increase in salivary cortisol, which lasted for 135 min. Small bowel water content (SBWC) rose from baseline, peaking at 45 min after fructose ingestion, whereas breath hydrogen peaked later, at 75 min. The area under the curve for SBWC from -15 min to 135 min was significantly lower after CRF compared with saline [mean difference: 5911 mL · min (95% CI: 18.4, 11,803 mL · min), P = 0.049]. Considering all subjects, the percentage change in ascending colon volume rose significantly after CRF. This increase was significant for male (P = 0.026), but not female, volunteers. CONCLUSIONS: CRF constricts the small bowel and increases fructose malabsorption, as shown by increased ascending colon volumes. This mechanism may help to explain the increased sensitivity of some stressed individuals to fructose malabsorption. This trial was registered at clinicaltrials.gov as NCT01763281.