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Previous studies associated plasma cathepsin D (CTSD) activity with hepatic insulin resistance in overweight and obese humans. Insulin resistance is a major feature of non-alcoholic fatty liver disease (NAFLD) and is one of the multiple hits determining the progression towards non-alcoholic steatohepatitis (NASH). In line, we have previously demonstrated that plasma CTSD levels are increased in NASH patients. However, it is not known whether insulin resistance associates with plasma CTSD activity in NAFLD. To increase our understanding regarding the mechanisms by which insulin resistance mediates NAFLD, fifty-five liver biopsy or MRI-proven NAFLD patients (BMI>25kg/m2) were included to investigate the link between plasma CTSD activity to insulin resistance in NAFLD. We concluded that HOMA-IR and plasma insulin levels are independently associated with plasma CTSD activity in NAFLD patients (standardized coefficient β: 0.412, 95% Cl: 0.142~0.679, p=0.004 and standardized coefficient β: 0.495, 95% Cl: 0.236~0.758, p=0.000, respectively). Together with previous studies, these data suggest that insulin resistance may link to NAFLD via elevation of CTSD activity in plasma. As such, these data pave the way for testing CTSD inhibitors as a pharmacological treatment of NAFLD.

Previously, we have shown that hepatic lipid accumulation induces the secretion of cathepsin D (CTSD), and that plasma CTSD levels are associated with increased inflammation and disease severity in nonalcoholic fatty liver disease (NAFLD). Although it is clear that the liver is a major source of plasma CTSD, it is unknown whether other metabolically active organs such as the muscle, also associate with plasma CTSD levels in NAFLD patients. Therefore, the aim of this study was to explore the relation between lipid accumulation in the muscle (myosteatosis) and plasma CTSD levels in forty-five NAFLD patients. We observed that hepatic steatosis positively associated with plasma CTSD levels, confirming the previously established link between plasma CTSD and the liver. Furthermore, a positive association between myosteatosis and plasma CTSD levels was observed, which was independent of sex, age, BMI, waist circumference and hepatic steatosis. By establishing a positive association between myosteatosis and plasma CTSD levels, our findings suggest that, in addition to the liver, the muscle is also linked to plasma CTSD levels in NAFLD patients. The observed link between myosteatosis and plasma CTSD levels supports the concept of a significant role of the skeletal muscle in metabolic disturbances in metabolic syndrome-related disorders.

Ectopic adipose tissues (EAT) are present adjacent to many organs and have predominantly been described in overweight and obesity. They have been suggested to be related to fatty acid overflow and to have harmful effects. The objective of this semi-comprehensive review is to explore whether EAT may play a supportive role rather than interfering with its function, when the adjacent organ is challenged metabolically and functionally. EAT are present adhered to different tissues or organs, including lymph nodes, heart, kidney, ovaries and joints. In this review, we only focused on epicardial, perinodal, and peritumoral fat since these locations have been studied in more detail. Evidence was found that EAT volume significantly increased, associated with chronic metabolic challenges of the corresponding tissue. In vitro evidence revealed transfer of fatty acids from peritumoral and perinodal fat to the adjacent tissue. Cytokine expression in these EAT is upregulated when the adjacent tissue is challenged. In these tissues, glycolysis is enhanced, whereas fatty acid oxidation is increased. Together with more direct evidence, this shows that glucose is oxidized to a lesser degree, but used to support anabolic metabolism of the adjacent tissue. In these situations, browning occurs, resulting from upregulation of anabolic metabolism, stimulated by uncoupling proteins 1 and 2 and possibly 3. In conclusion, the evidence found is fragmented but the available data support the view that accumulation and browning of adipocytes adjacent to the investigated organs or tissues may be a normal physiological response promoting healing and (patho)physiological growth., Author(s): Toon J. I. De Munck [sup.1] [sup.2] , Peter B. Soeters [sup.2] [sup.3] , Ger H. Koek [sup.1] [sup.2] [sup.4] Author Affiliations: (1) Department of Internal Medicine, Division of [...]

Previous studies associated plasma cathepsin D (CTSD) activity with hepatic insulin resistance in overweight and obese humans. Insulin resistance is a major feature of non-alcoholic fatty liver disease (NAFLD) and is one of the multiple hits determining the progression towards non-alcoholic steatohepatitis (NASH). In line, we have previously demonstrated that plasma CTSD levels are increased in NASH patients. However, it is not known whether insulin resistance associates with plasma CTSD activity in NAFLD. To increase our understanding regarding the mechanisms by which insulin resistance mediates NAFLD, fifty-five liver biopsy or MRI-proven NAFLD patients (BMI>25kg/m2 ) were included to investigate the link between plasma CTSD activity to insulin resistance in NAFLD. We concluded that HOMA-IR and plasma insulin levels are independently associated with plasma CTSD activity in NAFLD patients (standardized coefficient β: 0.412, 95% Cl: 0.142~0.679, p=0.004 and standardized coefficient β: 0.495, 95% Cl: 0.236~0.758, p=0.000, respectively). Together with previous studies, these data suggest that insulin resistance may link to NAFLD via elevation of CTSD activity in plasma. As such, these data pave the way for testing CTSD inhibitors as a pharmacological treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Previously, we have shown that hepatic lipid accumulation induces the secretion of cathepsin D (CTSD), and that plasma CTSD levels are associated with increased inflammation and disease severity in nonalcoholic fatty liver disease (NAFLD). Although it is clear that the liver is a major source of plasma CTSD, it is unknown whether other metabolically active organs such as the muscle, also associate with plasma CTSD levels in NAFLD patients. Therefore, the aim of this study was to explore the relation between lipid accumulation in the muscle (myosteatosis) and plasma CTSD levels in forty-five NAFLD patients. We observed that hepatic steatosis positively associated with plasma CTSD levels, confirming the previously established link between plasma CTSD and the liver. Furthermore, a positive association between myosteatosis and plasma CTSD levels was observed, which was independent of sex, age, BMI, waist circumference and hepatic steatosis. By establishing a positive association between myosteatosis and plasma CTSD levels, our findings suggest that, in addition to the liver, the muscle is also linked to plasma CTSD levels in NAFLD patients. The observed link between myosteatosis and plasma CTSD levels supports the concept of a significant role of the skeletal muscle in metabolic disturbances in metabolic syndrome-related disorders. [ABSTRACT FROM AUTHOR]

Background and Aim: Intestinal permeability (IP) plays an important role in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). We assessed site-specific (gastroduodenum, small intestine, colon and whole gut) IP in NAFLD patients and healthy controls (HC) and its association with the degree of hepatic steatosis, hepatic fibrosis and dietary composition in these NAFLD patients., Methods: In vivo site-specific IP was analysed with a validated multi-sugar test in NAFLD patients and HC. Furthermore, in NAFLD patients, hepatic steatosis (chemical shift MRI), hepatic fibrosis (transient elastography) and dietary composition (food frequency questionnaire) were assessed., Results: Fifty-two NAFLD patients and forty-six HC were included in this study. Small intestinal (P <0.001), colonic (P = 0.004) and whole gut (P <0.001) permeability were increased in NAFLD patients compared to HC. Furthermore, colonic permeability (P = 0.029) was significantly higher in NAFLD patients with clinically significant fibrosis compared to those without. Colonic permeability remained positively associated with the presence of clinically significant fibrosis (P = 0.017) after adjustment for age, sex and BMI., Conclusion: Colonic permeability is increased in at least a subset of NAFLD patients compared to HC and is independently associated with clinically significant NAFLD fibrosis., Competing Interests: Conflict of interest None declared., (Copyright © 2022. Published by Elsevier Ltd.)

Background and Aim: Insulin resistance (IR) plays a central role in the complex pathophysiology of nonalcoholic fatty liver disease (NAFLD). IR is linked to fat infiltration in skeletal muscle (myosteatosis) and loss of skeletal muscle mass and function (sarcopenia). The clinical significance of myosteatosis in NAFLD is not well investigated. In this exploratory study we aimed to investigate the association between myosteatosis and NAFLD related hepatic and systemic variables in a well characterized NAFLD cohort., Methods: We cross-sectionally studied forty-five NAFLD patients. The muscle fat fraction (MFF) was measured with chemical shift gradient echo MRI. In addition, the hepatic fat fraction (MRI), liver stiffness (FibroScan) and appendicular skeletal muscle mass (Dual-energy X-ray absorptiometry) were analyzed., Results: The median hepatic fat fraction was 15.64% (IQR 12.05-25.13) and significant (F2-F3) liver fibrosis (liver stiffness ≥7kPa) was diagnosed in 18 NAFLD patients (40%). MFF was not correlated with hepatic fat fraction (r=-0.035, P=0.823) and did not differ between subjects with or without significant fibrosis (P=0.980). No patient was diagnosed with sarcopenia based on the skeletal muscle mass index. In a linear regression model, anthropometric parameters, including body mass index (BMI) (P=0.018) and total body fat percentage (P=0.005), were positively associated with MFF while no association with insulin resistance (HOMA-IR) was observed., Conclusion: Myosteatosis did not correlate with the degree of hepatic steatosis or fibrosis in this well characterized NAFLD cohort, but was positively correlated with total body fat percentage and BMI., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Brown adipose tissue (BAT) might be a beneficial mediator in the development and treatment of nonalcoholic steatohepatitis (NASH). We aim to evaluate the gene expression of BAT activity-related genes during the development and the dietary and surgical treatment of NASH. BAT was collected from male C57BL/6J mice that received a high fat-high sucrose diet (HF-HSD) or a normal chow diet (NCD) for 4 and 20 weeks (n=8-9 per dietary group and timepoint) and from mice that underwent dietary intervention (return to NCD) (n=8), roux-en-y gastric bypass (RYGB) (n=6), or sham procedure (n=6) after 12 weeks HF-HSD. Expression of BAT genes involved in lipid metabolism (Cd36 and Cpt1b; p<0.05) and energy expenditure (Ucp1 and Ucp3; p<0.05) were significantly increased after 4 weeks HF-HSD compared with NCD, whereas in the occurrence of NASH after 20 weeks HF-HSD no difference was observed. We observed no differences in gene expression regarding lipid metabolism or energy expenditure at 8 weeks after dietary intervention (no NASH) compared with HF-HSD mice (NASH), nor in mice that underwent RYGB compared with SHAM. However, dietary intervention and RYGB both decreased the BAT gene expression of inflammatory cytokines (Il1b, Tnf-α and MCP-1; p<0.05). Gene expression of the batokine neuregulin 4 was significantly decreased after 20 weeks HF-HSD (p<0.05) compared with NCD, but was restored by dietary intervention and RYGB (p<0.05). In conclusion, BAT is hallmarked by dynamic alterations in the gene expression profile during the development of NASH and can be modulated by dietary intervention and bariatric surgery., Competing Interests: The authors declare that they have no conflict of interest., (Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany.)