Management of cardiovascular risk in patients with metabolic dysfunction-associated steatotic liver disease.

The novel term Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is proposed to replace non-alcoholic fatty liver disease (NAFLD) to highlight the close association with the metabolic syndrome. MASLD encompasses patients with liver steatosis and at least one of five cardiometabolic risk factors which implies that these patients are at increased risk of cardiovascular disease (CVD). Indeed, the prevalence of CVD in MASLD patients is increased and CVD is recognized as the most common cause of death in MASLD patients. We here present an update on the pathophysiology of CVD in MASLD, discuss the risk factors, and suggest screening for CVD in patients with MASLD. Currently, there is no FDA-approved pharmacological treatment for MASLD, and no specific treatment recommended for CVD in patients with MASLD. Thus, the treatment strategy is based on weight loss and a reduction and treatment of CVD risk factors. We recommend screening of MASLD patients for CVD using the SCORE2 system with guidance to specific treatment algorithms. In all patients with CVD risk factors, lifestyle intervention to induce weight loss through diet and exercise is recommended. Especially a Mediterranean diet may improve hyperlipidemia and if further treatment is needed, statins should be used as first-line treatment. Further, anti-hypertensive drugs should be used to treat hypertension. With the epidemic of obesity and type 2 diabetes mellitus (T2DM) the risk of MASLD and CVD is expected to increase, and preventive measures, screening, and effective treatments are highly needed to reduce morbidity and mortality in MASLD patients.

Effects of lifestyle intervention on IGF-1, IGFBP-3, and insulin resistance in children with obesity with or without metabolic-associated fatty liver disease.

Obesity is a strong predictor for metabolic associated fatty liver disease (MAFLD), which has been associated with decreased insulin like growth factor 1 (IGF-1). In obesity, weight loss increases growth hormone secretion, but this is not unequivocally associated with increases in serum IGF-1 and IGF binding protein-3 (IGFBP-3). We studied the changes in the IGF axis in relation to weight loss and improvement in insulin resistance in children with or without MALFD after 10 weeks of lifestyle intervention at a weight loss camp (WLC). We investigated 113 (66 females) Caucasian children with obesity, median age 12.4 (range 7.3-14.6) years, before and after 10 weeks of lifestyle intervention at a WLC. We investigated children who was either MAFLD positive (n = 54) or negative (n = 59) before and after WLC. Children with MAFLD had lower baseline IGF-1 (249 ± 112 vs 278 ± 107 µg/l, P = 0.048), whereas the IGF-1/IGFBP-3 molar ratio was similar to children without MAFLD (19.4 ± 6.6 vs. 21.8 ± 6.6%, P = 0.108). When all children were considered as one group, WLC decreased SDS-BMI and HOMA-IR (P < 0.001, both) and increased IGF-1 (264 ± 110 vs 285 ± 108 µg/l, P < 0.001) and the IGF/IGFBP-3 molar ratio (20.7 ± 6.7 vs 22.4 ± 6.1%, P < 0.001). When categorized according to liver status, IGF-1 increased significantly in children with MAFLD (P = 0.008) and tended to increase in children without MAFLD (P = 0.052).   Conclusions: Ten weeks of lifestyle intervention decreased insulin resistance and improved the IGF axis. We observed slight differences in the IGF axis in relation to MAFLD status. This suggests that the IGF axis is primarily influenced by insulin resistance rather than MAFLD status. What is New: • Weight loss decreases insulin resistance and subsequently increases the IGF axis in children with obesity. • Children with MAFLD had an aberration in the IGF axis compared to their MAFLD negative counter parts and the IGF axis was primarily influenced by the decreased BMI-SDS and insulin resistance, rather than MAFLD status. What is Known: • NAFLD has previously been associated with reduced serum IGF-1 concentrations. • Data on the impact of MAFLD and aberrations in the growth hormone and IGF axis and the effects of lifestyle interventions in children are limited.

Preserved liver regeneration capacity after partial hepatectomy in rats with non-alcoholic steatohepatitis.

AIM: To evaluate the liver regeneration capacity (LRC) after partial hepatectomy (PH) in experimental non-alcoholic steatohepatitis (NASH). METHODS: Fifty-four female rats were fed a high-fat, high-cholesterol diet (HFCD, 65% fat, 1% cholesterol) or standard diet (STD) for 16 wk. A 70% PH was performed and the animals were euthanised before PH or 2 or 5 d post-PH. LRC was evaluated using: The total number of Ki-67 positive hepatocytes in the caudate lobe, N(Ki-67, lobe) evaluated in a stereology-based design, the regenerated protein ratio (RPR), prothrombin-proconvertin ratio (PP), and mRNA expression of genes related to regeneration. RESULTS: The HFCD NASH model showed significant steatosis with ballooning and inflammation, while no fibrosis was present. Mortality was similar in HFCD and STD animals following PH. HFCD groups were compared to respective STD groups and HFCD animals had a significantly elevated alanine transaminase at baseline (P < 0.001), as well as a significantly elevated bilirubin at day 2 after PH (P < 0.05). HFCD animals had a higher N(Ki-67, lobe) at baseline, (P < 0.0001), day 2 after PH (P = 0.06) and day 5 after PH (P < 0.025). We found no significant difference in RPR or PP neither 2 or 5 d post-PH. Expression of liver regeneration genes (e.g., hepatic growth factor) was higher at both day 2 and 5 post-PH in HFCD groups (P < 0.05). CONCLUSION: NASH rats had a preserved LRC after hepatectomy when compared to STD rats. The methods and models of NASH are essential in understanding and evaluating LRC.

Effect of resveratrol on experimental non-alcoholic fatty liver disease depends on severity of pathology and timing of treatment.

BACKGROUND AND AIM: Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease with few therapeutic options. Resveratrol (RSV) prevents the development of steatosis in a number of experimental fatty liver (non-alcoholic fatty liver [NAFL]) models, but the preventive or therapeutic effects on experimental NASH are not yet clarified, and clinical results on non-alcoholic fatty liver disease are ambiguous. Thus, we aimed to compare the RSV-mediated preventive and therapeutic effects on experimental NAFL and NASH. METHODS: We used a high-fat (HF) diet to generate a rat NAFL model and a high-fat, high-cholesterol (HFC) diet to generate a rat NASH model. The preventive and therapeutic potential of RSV was tested by adding RSV to the HF and HFC diet from study start or after 1 week of the diets. Animals were sacrificed after 8 weeks with appropriate controls. Blood and liver were harvested for analysis, including measurement of RSV metabolites. RESULTS: Resveratrol reduced the development of histological steatosis (P = 0.03) and partly triglyceride accumulation (fold change reduced from 3.6 to 2.4, P = 0.08) in the male NAFL model, although effects were moderate. In NASH prevention, RSV reduced the accumulation of triglyceride in hepatic tissue (P < 0.01), while there was no effect on biochemical, histopathological, or transcriptional NASH changes. Further, RSV had no therapeutic effect on established NASH. We found RSV metabolites but no parent RSV in serum or liver tissue, confirming low bioavailability. CONCLUSIONS: These experimental findings suggest that a weak hepatic benefit of RSV treatment is seen in prevention of steatosis only.