Excessive fat accumulation in the body causes overweight and obesity. To date, research has confirmed that there are two types of adipose tissue with opposing functions: lipid-storing white adipose ...tissue (WAT) and lipid-burning brown adipose tissue (BAT). After the rediscovery of the presence of metabolically active BAT in adults, BAT has received increasing attention especially since activation of BAT is considered a promising way to combat obesity and associated comorbidities. It has become clear that energy homeostasis differs between the sexes, which has a significant impact on the development of pathological conditions such as type 2 diabetes. Sex differences in BAT activity may contribute to this and, therefore, it is important to address the underlying mechanisms that contribute to sex differences in BAT activity. In this review, we discuss the role of sex hormones in the regulation of BAT activity under physiological and some pathological conditions. Given the increasing number of studies suggesting a crosstalk between sex hormones and the hypothalamic-pituitary-adrenal axis in metabolism, we also discuss this crosstalk in relation to sex differences in BAT activity.
The liver is generally considered as a relatively homogeneous organ containing four different cell types. It is however well-known that the liver is not homogeneous and consists of clearly demarcated ...metabolic zones. Hepatocytes from different zones show phenotypical heterogeneity in metabolic features, leading to zonation of metabolic processes across the liver acinus. Zonation of processes involved in glucose and fatty acid metabolism is rather flexible and therefore prone to change under (patho)physiological conditions.
Hepatic zonation appears to play an important role in the segregation of the different metabolic pathways in the liver. As a consequence, perturbations in metabolic zonation may be a part of metabolic liver diseases. The metabolic syndrome is characterized by the inability of insulin to adequately suppress hepatic gluconeogenesis, leading to hyperglycemia, hyperinsulinemia and eventually to type II diabetes. As insulin promotes lipogenesis through the transcription factor sterol regulatory element binding protein (SREBP)-1c, one would expect that lipogenesis should also be impaired in insulin-resistant states. However, in the metabolic syndrome hepatic de novo lipogenesis is increased, leading to hyperlipidemia and hepatosteatosis, primarily in the pericentral zone. These observations suggest the co-existence of insulin resistant glucose metabolism and insulin sensitive lipid metabolism in the metabolic syndrome. Here we provide a theoretical framework to explain this so-called ‘insulin signaling paradox’ in the context of metabolic zonation of the liver.
•Zonation of metabolic pathways in the liver has major consequences for lipid and carbohydrate metabolism.•Hepatic zonation is regulated via a complex interplay of signaling pathways with a major role for the Wnt pathway.•Zonation may explain insulin resistance of hepatic glucose metabolism in the face of insulin sensitive lipid metabolism.
Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction) associated liver disease (MAFLD), is, with a global prevalence of 25%, the most common liver disorder worldwide. NAFLD comprises a ...spectrum of liver disorders ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and eventually end-stage liver disease. The cause of NAFLD is multifactorial with genetic susceptibility and an unhealthy lifestyle playing a crucial role in its development. Disrupted hepatic lipid homeostasis resulting in hepatic triglyceride accumulation is an hallmark of NAFLD. This disruption is commonly described based on four pathways concerning 1) increased fatty acid influx, 2) increased
lipogenesis, 3) reduced triglyceride secretion, and 4) reduced fatty acid oxidation. More recently, lipophagy has also emerged as pathway affecting NAFLD development and progression. Lipophagy is a form of autophagy (i.e. controlled autolysosomal degradation and recycling of cellular components), that controls the breakdown of lipid droplets in the liver. Here we address the role of hepatic lipid homeostasis in NAFLD and specifically review the current literature on lipophagy, describing its underlying mechanism, its role in pathophysiology and its potential as a therapeutic target.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low density lipoprotein receptor (LDLR) protein levels and function. Loss of PCSK9 increases LDLR levels in liver and reduces plasma ...LDL cholesterol (LDLc), whereas excess PCSK9 activity decreases liver LDLR levels and increases plasma LDLc. Here, we have developed active, cross-species, small interfering RNAs (siRNAs) capable of targeting murine, rat, nonhuman primate (NHP), and human PCSK9. For in vivo studies, PCSK9 and control siRNAs were formulated in a lipidoid nanoparticle (LNP). Liver-specific siRNA silencing of PCSK9 in mice and rats reduced PCSK9 mRNA levels by 50-70%. The reduction in PCSK9 transcript was associated with up to a 60% reduction in plasma cholesterol concentrations. These effects were shown to be mediated by an RNAi mechanism, using 5'-RACE. In transgenic mice expressing human PCSK9, siRNAs silenced the human PCSK9 transcript by >70% and significantly reduced PCSK9 plasma protein levels. In NHP, a single dose of siRNA targeting PCSK9 resulted in a rapid, durable, and reversible lowering of plasma PCSK9, apolipoprotein B, and LDLc, without measurable effects on either HDL cholesterol (HDLc) or triglycerides (TGs). The effects of PCSK9 silencing lasted for 3 weeks after a single bolus i.v. administration. These results validate PCSK9 targeting with RNAi therapeutics as an approach to specifically lower LDLc, paving the way for the development of PCSK9-lowering agents as a future strategy for treatment of hypercholesterolemia.
Background
Exercise is an effective strategy for the prevention and regression of hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD), but it is unclear whether it can reduce ...advanced stages of NAFLD, i.e., steatohepatitis and liver fibrosis. Furthermore, it is not evident which modality of exercise is optimal to improve/attenuate NAFLD.
Objectives
The aim is to systematically review evidence for the effect of aerobic exercise (AE) on NAFLD, in particular non-alcoholic steatohepatitis (NASH) and liver fibrosis.
Methods
A systematic literature search was conducted in Medline and Embase. Studies were screened and included according to predefined criteria, data were extracted, and the quality was assessed by Cochrane risk of bias tools by two researchers independently according to the protocol registered in the PROSPERO database (CRD42021270059). Meta-analyses were performed using a bivariate random-effects model when there were at least three randomized intervention studies (RCTs) with similar intervention modalities and outcome.
Results
The systematic review process resulted in an inclusion a total of 24 studies, 18 RCTs and six non-RCTs, encompassing 1014 patients with NAFLD diagnosed by histological or radiological findings. Studies were grouped based on the type of AE: moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT). A total of twelve meta-analyses were conducted. Compared to controls, MICT resulted in a mean difference (MD) in the NAFLD biomarkers alanine transaminase (ALT) and aspartate aminotransferase (AST) of -3.59 (CI: -5.60, -1.59, p<0.001) and -4.05 (CI: -6.39, -1.71, p<0.001), respectively. HIIT resulted in a MD of -4.31 (95% CI: -9.03, 0.41, p=0.07) and 1.02 (95% CI: -6.91, 8.94, p=0.8) for ALT and AST, respectively. Moreover, both AE types compared to controls showed a significantly lower magnetic resonance spectroscopy (MRS) determined liver fat with a MD of -5.19 (95% CI: -7.33, -3.04, p<0.001) and -3.41 (95% CI: -4.74, -2.08, p<0.001), for MICT and HIIT respectively. MICT compared to controls resulted in a significantly higher cardiorespiratory fitness (MD: 4.43, 95% CI: 0.31, 8.55, p=0.03).
Conclusion
Liver fat is decreased by AE with a concomitant decrease of liver enzymes. AE improved cardiorespiratory fitness. Further studies are needed to elucidate the impact of different types of AE on hepatic inflammation and fibrosis.
Systematic Review Registration
https://www.crd.york.ac.uk/prospero/
, identifier (CRD42021270059).
The farnesoid X receptor (FXR) is a bile acid (BA)-activated nuclear receptor that plays a major role in the regulation of BA and lipid metabolism. Recently, several studies have suggested a ...potential role of FXR in the control of hepatic carbohydrate metabolism, but its contribution to the maintenance of peripheral glucose homeostasis remains to be established. FXR-deficient mice display decreased adipose tissue mass, lower serum leptin concentrations, and elevated plasma free fatty acid levels. Glucose and insulin tolerance tests revealed that FXR deficiency is associated with impaired glucose tolerance and insulin resistance. Moreover, whole-body glucose disposal during a hyperinsulinemic euglycemic clamp is decreased in FXR-deficient mice. In parallel, FXR deficiency alters distal insulin signaling, as reflected by decreased insulin-dependent Akt phosphorylation in both white adipose tissue and skeletal muscle. Whereas FXR is not expressed in skeletal muscle, it was detected at a low level in white adipose tissue in vivo and induced during adipocyte differentiation in vitro. Moreover, mouse embryonic fibroblasts derived from FXR-deficient mice displayed impaired adipocyte differentiation, identifying a direct role for FXR in adipocyte function. Treatment of differentiated 3T3-L1 adipocytes with the FXR-specific synthetic agonist GW4064 enhanced insulin signaling and insulin-stimulated glucose uptake. Finally, treatment with GW4064 improved insulin resistance in genetically obese ob/ob mice in vivo. Although the underlying molecular mechanisms remain to be unraveled, these results clearly identify a novel role of FXR in the regulation of peripheral insulin sensitivity and adipocyte function. This unexpected function of FXR opens new perspectives for the treatment of type 2 diabetes.
In recent years, the human gut microbiome has been found to influence a multitude of non-communicable diseases such as cardiovascular disease and metabolic syndrome, with its components type 2 ...diabetes mellitus and obesity. It is recognized to be mainly influenced by environmental factors, such as lifestyle, but also genetics may play a role. The interaction of gut microbiota and obesity has been widely studied, but in regard to non-alcoholic fatty liver disease (NAFLD) as a manifestation of obesity and insulin resistance, the causal role of the gut microbiome has not been fully established. The mechanisms by which the gut microbiome influences lipid accumulation, inflammatory responses, and occurrence of fibrosis in the liver are a topic of active research.
In addition, the influence of exercise on gut microbiome composition is also being investigated. In clinical trials, exercise reduced hepatic steatosis independently of weight reduction. Other studies indicate that exercise may modulate the gut microbiome. This puts forward the question whether exercise could mediate its beneficial effects on NAFLD via changes in gut microbiome. Yet, the specific mechanisms underlying this potential connection are largely unknown. Thus, associative evidence from clinical trials, as well as mechanistic studies in vivo are called for to elucidate the relationship between exercise and the gut microbiome in NAFLD. Here, we review the current literature on exercise and the gut microbiome in NAFLD.
Familial hypercholesterolemia is characterised by high low-density lipoprotein-cholesterol levels and is caused by a pathogenic variant in LDLR, APOB or PCSK9. We investigated which proportion of ...suspected familial hypercholesterolemia patients was genetically confirmed, and whether this has changed over the past 20 years in The Netherlands.
Targeted next-generation sequencing of 27 genes involved in lipid metabolism was performed in patients with low-density lipoprotein-cholesterol levels greater than 5 mmol/L who were referred to our centre between May 2016 and July 2018. The proportion of patients carrying likely pathogenic or pathogenic variants in LDLR, APOB or PCSK9, or the minor familial hypercholesterolemia genes LDLRAP1, ABCG5, ABCG8, LIPA and APOE were investigated. This was compared with the yield of Sanger sequencing between 1999 and 2016.
A total of 227 out of the 1528 referred patients (14.9%) were heterozygous carriers of a pathogenic variant in LDLR (80.2%), APOB (14.5%) or PCSK9 (5.3%). More than 50% of patients with a Dutch Lipid Clinic Network score of 'probable' or 'definite' familial hypercholesterolemia were familial hypercholesterolemia mutation-positive; 4.8% of the familial hypercholesterolemia mutation-negative patients carried a variant in one of the minor familial hypercholesterolemia genes. The mutation detection rate has decreased over the past two decades, especially in younger patients in which it dropped from 45% in 1999 to 30% in 2018.
A rare pathogenic variant in LDLR, APOB or PCSK9 was identified in 14.9% of suspected familial hypercholesterolemia patients and this rate has decreased in the past two decades. Stringent use of clinical criteria algorithms is warranted to increase this yield. Variants in the minor familial hypercholesterolemia genes provide a possible explanation for the familial hypercholesterolemia phenotype in a minority of patients.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates the expression of LDL receptor (LDLR) protein. Gain-of-function mutations in PCSK9 cause ...hypercholesterolemia, and loss-of-function mutations result in lower plasma LDL-cholesterol. Here, we investigate the kinetics and metabolism of circulating PCSK9 relative to tissue levels of LDLRs. The administration of recombinant human PCSK9 (32 μg) to mice by a single injection reduced hepatic LDLRs by ∼90% within 60 min, and the receptor levels returned to normal within 6 h. The half-life of the PCSK9 was estimated to be ∼5 min. Continuous infusion of PCSK9 (32 μg/h) into wild-type mice caused a ∼90% reduction in hepatic LDLRs within 2 h and no associated change in the level of LDLR in the adrenals. Parallel studies were performed using a catalytically inactive form of PCSK9, PCSK9(S386A), and similar results were obtained. Infusion of PCSK9(D374Y), a gain-of-function mutation, resulted in accelerated clearance of the mutant PCSK9 and a greater reduction in hepatic LDLRs. Combined, these data suggest that exogenously administrated PCSK9 in plasma preferentially reduces LDLR protein levels in liver at concentrations found in human plasma and that PCSK9's action on the LDLR is not dependent on catalytic activity in vivo.
Familial autosomal dominant hypercholesterolemia is associated with high risk for cardiovascular accidents and is related to mutations in the low density lipoprotein receptor or its ligand ...apolipoprotein B (apoB). Mutations in a third gene, proprotein convertase subtilisin kexin 9 (PCSK9), were recently associated to this disease. PCSK9 acts as a natural inhibitor of the low density lipoprotein receptor pathway, and both genes are regulated by depletion of cholesterol cell content and statins, via sterol regulatory element-binding protein (SREBP). Here we investigated the regulation of PCSK9 gene expression during nutritional changes. We showed that PCSK9 mRNA quantity is decreased by 73% in mice after 24 h of fasting, leading to a 2-fold decrease in protein level. In contrast PCSK9 expression was restored upon high carbohydrate refeeding. PCSK9 mRNA increased by 4–5-fold in presence of insulin in rodent primary hepatocytes, whereas glucose had no effect. Moreover, insulin up-regulated hepatic PCSK9 expression in vivo during a hyperinsulinemic-euglycemic clamp in mice. Adenoviral mediated overexpression of a dominant or negative form of SREBP-1c confirmed the implication of this transcription factor in insulin-mediated stimulation of PCSK9 expression. Liver X receptor agonist T0901317 also regulated PCSK9 expression via this same pathway (a 2-fold increase in PCSK9 mRNA of primary hepatocytes cultured for 24 h in presence of 1 μm T0901317). As our last investigation, we isolated PCSK9 proximal promoter and verified the functionality of a SREBP-1c responsive element located from 335 bp to 355 bp upstream of the ATG. Together, these results show that PCSK9 expression is regulated by nutritional status and insulinemia.
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