Suppression of intestinal Ticam1 ameliorated MASH via Akkermansia muciniphila QAA37749.1 mediated betaine transformation.

Background & Aims: Gut inflammation caused by diets could damage the intestinal barrier, which increases the liver exposition to pathogenic substances. Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 (Ticam1) is a key molecule in the Toll-like receptors (TLRs) pathway, which is important for the immune defense against pathogens such as bacteria or viruses. In this study, mouse intestinal epithelial cell (IEC) Ticam1 was knocked out to suppress the intestinal inflammation response in metabolic dysfunction-associated steatohepatitis (MASH) to investigate its influence on the development of MASH.

The role of forkhead box M1-methionine adenosyltransferase 2 A/2B axis in liver inflammation and fibrosis.

Methionine adenosyltransferase 2 A (MAT2A) and MAT2B are essential for hepatic stellate cells (HSCs) activation. Forkhead box M1 (FOXM1) transgenic mice develop liver inflammation and fibrosis. Here we examine if they crosstalk in male mice.

Hepatocyte programmed cell death: the trigger for inflammation and fibrosis in metabolic dysfunction-associated steatohepatitis.

By replacing and removing defective or infected cells, programmed cell death (PCD) contributes to homeostasis maintenance and body development, which is ubiquitously present in mammals and can occur at any time. Besides apoptosis, more novel modalities of PCD have been described recently, such as necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death. PCD not only regulates multiple physiological processes, but also participates in the pathogenesis of diverse disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD).

Repurposing of the analgesic Neurotropin for MASLD/MASH treatment.

Background: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased in recent decades. Approximately 25% of patients with MASLD progress to metabolic dysfunction-associated steatohepatitis, which is characterized by hepatic steatosis plus hepatocyte damage, inflammation, and fibrosis. We previously reported that Neurotropin (NTP), a drug used for relieving pain in Japan and China, inhibits lipid accumulation in hepatocytes by preventing mitochondrial dysfunction.

Unveiling the cancer risk nexus of the steatotic liver.

Steatotic liver, characterized by the accumulation of fat in the liver, poses significant health risks including metabolic dysfunction-associated steatotic liver disease (MASLD) and an elevated risk of primary liver cancer. Emerging evidence indicates a robust association between steatotic liver and increased susceptibility to extrahepatic primary cancers and their metastases. The deposition of fat induces dynamic changes in hepatic microenvironments, thereby fostering inflammation and immune responses that enhance liver metastasis from extrahepatic primary cancers.

S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver.

MCJ (Methylation-Controlled J protein), an endogenous repressor of the mitochondrial respiratory chain, is upregulated in multiple liver diseases but little is known about how it is regulated. S-adenosylmethionine (SAMe), the biological methyl donor, is frequently depleted in chronic liver diseases. Here, we show that SAMe negatively regulates MCJ in the liver.

Hepatic prohibitin 1 and methionine adenosyltransferase α1 defend against primary and secondary liver cancer metastasis.

Background & Aims: The liver is a common site of cancer metastasis, most commonly from colorectal cancer, and primary liver cancers that have metastasized are associated with poor outcomes. The underlying mechanisms by which the liver defends against these processes are largely unknown. Prohibitin 1 (PHB1) and methionine adenosyltransferase 1A (MAT1A) are highly expressed in the liver.

In Vivo and In Vitro Models to Study Liver Fibrosis: Mechanisms and Limitations.

Liver fibrosis is a common result of liver injury owing to various kinds of chronic liver diseases. A deeper understanding of the pathophysiology of liver fibrosis and identifying potential therapeutic targets of liver fibrosis is important because liver fibrosis may progress to advanced liver diseases, such as cirrhosis and hepatocellular carcinoma. Despite numerous studies, the underlying mechanisms of liver fibrosis remain unclear.

Experimental Workflow for Preclinical Studies of Human Antifibrotic Therapies.

Chronic liver diseases accompanied by liver fibrosis have caused significant morbidity and mortality in the world with increasing prevalence. Nonetheless, there are no approved antifibrotic therapies. Although numerous preclinical studies showed satisfactory results in targeting fibrotic pathways, these animal studies have not led to success in humans.

Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment.

Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Fatty liver promotes liver metastasis, but the underlying mechanism remains unclear. We demonstrated that hepatocyte-derived extracellular vesicles (EVs) in fatty liver enhanced the progression of CRC liver metastasis by promoting oncogenic Yes-associated protein (YAP) signaling and an immunosuppressive microenvironment.

Hyaluronan in liver fibrosis: basic mechanisms, clinical implications, and therapeutic targets.

Hyaluronan (HA), also known as hyaluronic acid, is a glycosaminoglycan that is a critical component of the extracellular matrix (ECM). Production and deposition of ECM is a wound-healing response that occurs during chronic liver disease, such as cirrhosis. ECM production is a sign of the disease progression of fibrosis.

Capsaicin receptor TRPV1 maintains quiescence of hepatic stellate cells in the liver via recruitment of SARM1.

Background & Aims: Capsaicin receptor, also known as transient receptor potential vanilloid 1 (TRPV1), is involved in pain physiology and neurogenic inflammation. Herein, we discovered the presence of TRPV1 in hepatic stellate cells (HSCs) and aimed to delineate its function in this cell type and liver fibrosis.

Methods: TRPV1 expression was examined in liver biopsies from patients with liver fibrosis using quantitative real-time PCR and immunostaining.

Breast cancer liver metastasis: Pathogenesis and clinical implications.

Breast cancer is the most common malignant disease in female patients worldwide and can spread to almost every place in the human body, most frequently metastasizing to lymph nodes, bones, lungs, liver and brain. The liver is a common metastatic location for solid cancers as a whole, and it is also the third most common metastatic site for breast cancer. Breast cancer liver metastasis (BCLM) is a complex process.

Serum Glial Cell Line-Derived Neurotrophic Factor (sGDNF) Is a Novel Biomarker in Predicting Cirrhosis in Patients with Chronic Hepatitis B.

Objectives: We assessed the potential of glial cell line-derived neurotrophic factor (GDNF) as a useful biomarker to predict cirrhosis in chronic hepatitis B (CHB) patients.

Methods: A total of 735 patients from two medical centers (385 CHB patients and 350 healthy controls) were included to determine the association of serum and tissue GDNF levels with biopsy-proven cirrhosis. The diagnostic accuracy of serum GDNF (sGDNF) was estimated and compared with other indices of cirrhosis.

Hyaluronan synthase 2, a target of miR-200c, promotes carbon tetrachloride-induced acute and chronic liver inflammation via regulation of CCL3 and CCL4.

Liver fibrosis occurs during wound healing after repeated liver injury and is characterized by extensive extracellular matrix deposition. We previously identified hyaluronan synthase 2 (HAS2) as a driver of liver fibrosis and hepatic stellate cell (HSC) activation. Developing strategies to suppress HSC activation is key to alleviating liver fibrosis, and HAS2 is an attractive candidate for intervention.

Depletion of mitochondrial methionine adenosyltransferase α1 triggers mitochondrial dysfunction in alcohol-associated liver disease.

MATα1 catalyzes the synthesis of S-adenosylmethionine, the principal biological methyl donor. Lower MATα1 activity and mitochondrial dysfunction occur in alcohol-associated liver disease. Besides cytosol and nucleus, MATα1 also targets the mitochondria of hepatocytes to regulate their function.

Hepatocyte TGF-β Signaling Inhibiting WAT Browning to Promote NAFLD and Obesity Is Associated With Let-7b-5p.

Transforming growth factor beta (TGF-β) signaling in hepatocytes promotes steatosis and body weight gain. However, processes that TGF-β signaling in hepatocytes promote pathological body weight gain in nonalcoholic fatty liver disease (NAFLD) are incompletely understood. Obesity and NAFLD were induced by 16 weeks of feeding a high-fat diet (HFD) in hepatocyte-specific TGF-β receptor II-deficient (Tgfbr2 ) and Tgfbr2 mice.

TAK1: A Molecular Link Between Liver Inflammation, Fibrosis, Steatosis, and Carcinogenesis.

Chronic insult and persistent injury can cause liver inflammation, fibrosis, and carcinogenesis; it can also be associated with metabolic disorders. Identification of critical molecules that link the process of inflammation and carcinogenesis will provide prospective therapeutic targets for liver diseases. Rapid advancements in gene engineering technology have allowed the elucidation of the underlying mechanism of transformation, from inflammation and metabolic disorders to carcinogenesis.

Deregulated 14-3-3ζ and methionine adenosyltransferase α1 interplay promotes liver cancer tumorigenesis in mice and humans.

Methionine adenosyltransferase 1A (MAT1A) is a tumor suppressor downregulated in hepatocellular carcinoma and cholangiocarcinoma, two of the fastest rising cancers worldwide. We compared MATα1 (protein encoded by MAT1A) interactome in normal versus cancerous livers by mass spectrometry to reveal interactions with 14-3-3ζ. The MATα1/14-3-3ζ complex was critical for the expression of 14-3-3ζ.

Modeling alcohol-associated liver disease in a human Liver-Chip.

Alcohol-associated liver disease (ALD) is a global health issue and leads to progressive liver injury, comorbidities, and increased mortality. Human-relevant preclinical models of ALD are urgently needed. Here, we leverage a triculture human Liver-Chip with biomimetic hepatic sinusoids and bile canaliculi to model ALD employing human-relevant blood alcohol concentrations (BACs) and multimodal profiling of clinically relevant endpoints.