Effect of Silibinin on Human Pancreatic Lipase Inhibition and Gut Microbiota in Healthy Volunteers: A Randomized Controlled Trial.

Thistle () has been traditionally employed for liver protection. However, we recently identified silibinin, the main bioactive compound of thistle extract, as an in vitro pancreatic lipase inhibitor, which suggested a potential role as an anti-obesity agent. This study aimed to assess, in vivo, the efficacy, safety, and effects of silibinin on human lipase.

Loss of protects against MASLD alone or with alcohol intake by preserving lipid homeostasis.

Background & Aims: Expression of P21, encoded by the gene, has been associated with fibrosis progression in steatotic liver disease (SLD); however, the underlying mechanisms remain unknown. In the present study, we investigated the function of CDKN1A in SLD.

Methods: expression levels were evaluated in different patient cohorts with SLD, fibrosis, and advanced chronic liver disease (ACLD).

Hepatic HKDC1 Deletion Alleviates Western Diet-Induced MASH in Mice.

The global prevalence of Metabolic dysfunction-associated steatohepatitis (MASH) has been rising sharply, closely mirroring the increasing rates of obesity and metabolic syndrome. MASH exhibits a strong sexual dimorphism where females are affected with more severe forms after menopause. Hexokinase domain-containing protein 1 (HKDC1) has recently been recognized for its role in liver diseases, where its expression is minimal under normal conditions but significantly increases in response to metabolic stressors like obesity and liver injury.

Landscape of antisense genes in the human genome and identification of new human hepatic antisense RNAs by long-read sequencing.

Background: Protein-coding genes have been considered the functional part of the genome, although they represent only 2% of the genome. In contrast, more than 90% of the genome produces non-coding RNA (ncRNA), including antisense (AS) genes, a type of long non-coding genes (encoding transcripts > 200 nucleotides) located on the opposite strand of coding genes. Therefore, antisense RNA (asRNA) can be complementary to the counterpart sense RNA, supporting a regulatory role with potential pathogenic consequences, as their deregulation has been associated with cardiovascular disease, cancer, and diabetes.

In Vitro Study of the Differential Anti-Inflammatory Activity of Dietary Phytochemicals upon Human Macrophage-like Cells as a Previous Step for Dietary Intervention.

Chronic inflammatory diseases pose a substantial health challenge globally, significantly contributing to morbidity and mortality. Addressing this issue requires the use of effective anti-inflammatory strategies with fewer side effects than those provoked by currently used drugs. In this study, a range of phytochemicals (phenolic di-caffeoylquinic acid (Di-CQA), flavonoid cyanidin-3,5-diglucoside (Cy3,5DiG), aromatic isothiocyanate sinalbin (SNB) and aliphatic isothiocyanate sulforaphane (SFN)) sourced from vegetables and fruits underwent assessment for their potential anti-inflammatory activity.

Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition that often progresses to more advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH). MASH is characterized by inflammation and hepatocellular ballooning, in addition to hepatic steatosis. Despite the relatively high incidence of MASH in the population and its potential detrimental effects on human health, this liver disease is still not fully understood from a pathophysiological perspective.

Therapeutic implications for sphingolipid metabolism in metabolic dysfunction-associated steatohepatitis.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), a leading cause of chronic liver disease, has increased worldwide along with the epidemics of obesity and related dysmetabolic conditions characterized by impaired glucose metabolism and insulin signaling, such as type 2 diabetes mellitus (T2D). MASLD can be defined as an excessive accumulation of lipid droplets in hepatocytes that occurs when the hepatic lipid metabolism is totally surpassed. This metabolic lipid inflexibility constitutes a central node in the pathogenesis of MASLD and is frequently linked to the overproduction of lipotoxic species, increased cellular stress, and mitochondrial dysfunction.

Triglyceride to HDL Cholesterol Ratio for the Identification of MASLD in Obesity: A Liver Biopsy-Based Case-Control Study.

Associations between dyslipidemia and metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. Previous studies have shown that the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio may be a surrogate marker of MASLD, assessed by liver ultrasound. However, no studies have evaluated the utility of this ratio according to biopsy-proven MASLD and its stages.

Proceedings of the 5th Meeting of Translational Hepatology, organized by the Spanish Association for the Study of the Liver (AEEH).

This is the summary report of the 5th Translational Hepatology Meeting, endorsed by the Spanish Association for the Study of the Liver (AEEH) and held in Seville, Spain, in October 2023. The meeting aimed to provide an update on the latest advances in the field of basic and translational hepatology, covering different molecular, cellular, and pathophysiological aspects of the most relevant clinical challenges in liver pathologies. This includes the identification of novel biomarkers and diagnostic tools, the understanding of the relevance of immune response and inflammation in liver diseases, the characterization of current medical approaches to reverse liver diseases, the incorporation of novel molecular insights through omics techniques, or the characterization of the impact of toxic and metabolic insults, as well as other organ crosstalk, in liver pathophysiology.

Revisiting liver metabolism through acetyl-CoA carboxylase inhibition.

Liver-targeted acetyl-coenzyme A (CoA) carboxylase (ACC) inhibitors in metabolic dysfunction-associated steatotic liver disease (MASLD) trials reveal notable secondary effects: hypertriglyceridemia and altered glucose metabolism, paradoxically with reduced hepatic steatosis. In their study, Deja et al. explored how hepatic ACC influences metabolism using different pharmacological and genetic methods, coupled with targeted metabolomics and stable isotope-based tracing techniques.

RNA expression changes driven by altered epigenetics status related to NASH etiology.

Non-alcoholic fatty liver disease (NAFLD) is a growing health problem due to the increased obesity rates, among other factors. In its more severe stage (NASH), inflammation, hepatocellular ballooning and fibrosis are present in the liver, which can further evolve to total liver dysfunction or even hepatocarcinoma. As a metabolic disease, is associated to environmental factors such as diet and lifestyle conditions, which in turn can influence the epigenetic landscape of the cells, affecting to the gene expression profile and chromatin organization.

The role of PCSK9 in metabolic dysfunction-associated steatotic liver disease and its impact on bariatric surgery outcomes.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely tied to obesity. The degree ranges from steatosis (MASL) and steatohepatitis (MASH) to liver cirrhosis. PCSK9 controls cholesterol and lipid particle transport to the liver.

A novel model for predicting diabetes remission after bariatric surgery based on the measurement of C-peptide and creatinine in serum: A pilot study.

Background And Aims: Bariatric surgery is effective for treating type 2 diabetes (T2D) in patients with obesity, although a significant proportion of these patients do not achieve diabetes remission after the surgery even after significant weight loss and metabolic improvement. C-peptide is a valuable marker of beta cell function and insulin secretion, but renal function must be considered when interpreting measurements in patients with T2D. The study aims to investigate the association of serum levels of C-peptide adjusted for creatinine with diabetes remission and glycemic target achievement after bariatric surgery in patients with obesity and T2D.

Lipidomic Analysis Reveals Alterations in Hepatic FA Profile Associated With MASLD Stage in Patients With Obesity.

Context: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the intracellular lipid accumulation in hepatocytes. Excess caloric intake and high-fat diets are considered to significantly contribute to MASLD development.

Objective: To evaluate the hepatic and serum fatty acid (FA) composition in patients with different stages of MASLD, and their relationship with FA dietary intake and MASLD-related risk factors.

Non-alcoholic fatty liver disease and diabetes mellitus as growing aetiologies of hepatocellular carcinoma.

Obesity-related complications such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are well-established risk factors for the development of hepatocellular carcinoma (HCC). This review provides insights into the molecular mechanisms that underlie the role of steatosis, hyperinsulinemia and hepatic inflammation in HCC development and progression. We focus on recent findings linking intracellular pathways and transcription factors that can trigger the reprogramming of hepatic cells.

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis.

Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl) intoxication and bile duct ligation (BDL).

NAD+ Precursors and Intestinal Inflammation: Therapeutic Insights Involving Gut Microbiota.

The oxidized form of nicotinamide adenine dinucleotide (NAD+) is a critical metabolite for living cells. NAD+ may act either as a cofactor for many cellular reactions as well as a coenzyme for different NAD+-consuming enzymes involved in the physiological homeostasis of different organs and systems. In mammals, NAD+ is synthesized from either tryptophan or other vitamin B3 intermediates that act as NAD+ precursors.

Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD.

Objective: Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes.

Methods: We studied the phenotype of wild-type and Sucnr1 mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid.

NOD-like receptors in the pathogenesis of metabolic (dysfunction)-associated fatty liver disease: Therapeutic agents targeting NOD-like receptors.

Background And Aims: In metabolic (dysfunction)-associated fatty liver disease (MAFLD), activation of inflammatory processes marks the transition of simple steatosis to steatohepatitis, which can further evolve to advanced fibrosis or hepatocellular carcinoma. Under the stress of chronic overnutrition, the innate immune system orchestrates hepatic inflammation through pattern recognition receptors (PRRs). Cytosolic PRRs that include NOD-like receptors (NLRs) are crucial for inducing inflammatory processes in the liver.

Environmental Exposure Science and Human Health.

Human health and environmental exposure form an inseparable binomial [...

Dihydrosphingolipids are associated with steatosis and increased fibrosis damage in non-alcoholic fatty liver disease.

Dihydrosphingolipids are lipids biosynthetically related to ceramides. An increase in ceramides is associated with enhanced fat storage in the liver, and inhibition of their synthesis is reported to prevent the appearance of steatosis in animal models. However, the precise association of dihydrosphingolipids with non-alcoholic fatty liver disease (NAFLD) is yet to be established.

New challenges in cholangiocarcinoma candidates for elective surgery: harnessing the microbiome dysbiosis.

Background: The gut microbiota, composed by several species of microorganisms, works to preserve the liver-gut homeostasis and plays an important role during digestion and absorption of nutrients, and in the immune response of the host. In this review, we analyzed the influence of microbiota in patients with cholangiocarcinoma (CCA) who were candidates for elective surgery.

Methods: A literature review was conducted to identify papers that provided empiric evidence to support that the altered microbiota composition (dysbiosis) is related also to CCA development.

Inherited Epigenetic Hallmarks of Childhood Obesity Derived from Prenatal Exposure to Obesogens.

Childhood obesity has reached epidemic levels in developed countries and is becoming a major cause for concern in the developing world. The causes of childhood obesity are complex and multifactorial, involving the interaction between individual genetics and environmental and developmental factors. Among the environmental factors, there is a growing interest in understanding the possible relationship between the so-called environmental obesogens and the development of obesity in children.