CAIP-Induced ROS Production Contributes to Sustaining Atherosclerotic Process Associated with Infection through Macrophages and Endothelial Cells Activation.

Several lines of evidence have linked the intestinal bacterium with the pathogenesis of atherosclerosis, identifying the Cinaedi Antigen Inflammatory Protein (CAIP) as a key virulence factor. Oxidative stress and inflammation are crucial in sustaining the atherosclerotic process and oxidized LDL (oxLDL) uptake. Primary human macrophages and endothelial cells were pre-incubated with 10 µM diphenyl iodonium salt (DPI) and stimulated with 20 µg/mL CAIP.

DGAT1 and DGAT2 Inhibitors for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Management: Benefits for Their Single or Combined Application.

Inhibiting diacylglycerol acetyltransferase (DGAT1, DGAT2) enzymes (iDGAT1, iDGAT2), involved in triglyceride (TG) synthesis, improves hepatic steatosis in metabolic dysfunction-associated steatotic liver disease (MASLD) patients. However, their potential synergism in disease onset (SLD) and progression (metabolic dysfunction-associated steatohepatitis, fibrosis) has been poorly explored. We investigated iDGAT1 and iDGAT2 efficacy, alone or combined (iDGAT1/2) on fat accumulation and hepatocellular injury in hepatocytes (HepG2) and on fibrogenic processes in hepatic stellate cells (LX2).

Hepatic and adipose tissue transcriptome analysis highlights a commonly deregulated autophagic pathway in severe MASLD.

Objective: The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly ramping up due to the spread of obesity, which is characterized by expanded and dysfunctional visceral adipose tissue (VAT). Previous studies have investigated the hepatic transcriptome across MASLD, whereas few studies have focused on VAT.

Methods: We performed RNA sequencing in 167 hepatic samples from patients with obesity and in a subset of 79 matched VAT samples.

A narrative review about cognitive impairment in metabolic Dysfunction-Associated liver disease (MASLD): Another matter to face through a holistic approach.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic hepatic disorder worldwide in both adults and children. It is well established that MASLD represents the hepatic manifestation of the metabolic syndrome whose definition includes the presence of obesity, type 2 diabetes (T2D), dyslipidemia, hypertension and hypercoagulability. All these conditions contribute to a chronic inflammatory status which may impact on blood brain barrier (BBB) integrity leading to an impaired function of central nervous system (CNS).

A novel gene signature to diagnose MASLD in metabolically unhealthy obese individuals.

Visceral adipose tissue (VAT) contributes to metabolic dysfunction-associated steatotic liver disease (MASLD), releasing lipogenic substrates and cytokines which promote inflammation. Metabolic healthy obese individuals (MHO) may shift towardsunhealthy ones (MUHO) who develop MASLD, although the mechanisms are still unexplained. Therefore, we aimed to identify dysfunctional pathways and transcriptomic signatures shared by liver and VAT and to outline novel obesity-related biomarkers which feature MASLD in MUHO subjects, at higher risk of progressive liver disease and extrahepatic comorbidities.

The I148M variant mitigates niacin beneficial effects: How the genetic screening in non-alcoholic fatty liver disease patients gains value.

Background: The PNPLA3 p.I148M impact on fat accumulation can be modulated by nutrients. Niacin (Vitamin B3) reduced triglycerides synthesis in and NAFLD models.

The Non-Invasive Assessment of Circulating D-Loop and mt-ccf Levels Opens an Intriguing Spyhole into Novel Approaches for the Tricky Diagnosis of NASH.

Nonalcoholic fatty liver disease (NAFLD) is the commonest liver disease worldwide affecting both adults and children. Nowadays, no therapeutic strategies have been approved for NAFLD management, and hepatic biopsy remains the gold standard procedure for its diagnosis. NAFLD is a multifactorial disease whose pathogenesis is affected by environmental and genetic factors, and it covers a spectrum of conditions ranging from simple steatosis up to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).

Expanding the phenotypic spectrum of non-alcoholic fatty liver disease and hypertriglyceridemia.

Background And Aims: Hypertriglyceridemia is a common feature of metabolic syndrome (MetS), as well as of non-alcoholic fatty liver disease (NAFLD), which is considered the hepatic manifestation of MetS. Fat accumulation in hepatocytes may alter mitochondrial homeostasis predisposing to advanced liver disease. Here, we report a case of a 40-year-old woman with early aggressive NAFLD due to severe hypertriglyceridemia that ensued from a combination of genetic variants and additional metabolic risk factors.

TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro Models.

Background & Aims: The I148M Patatin-like Phospholipase Domain-containing 3 (PNPLA3), the rs641738 in the Membrane bound O-acyltransferase domain containing 7-transmembrane channel-like 4 (MBOAT7-TMC4) locus, and the E167K Transmembrane 6 Superfamily Member 2 (TM6SF2) polymorphisms represent the main predisposing factors to nonalcoholic fatty liver disease (NAFLD) development and progression. We previously generated a full knockout of MBOAT7 in HepG2 cells (MBOAT7), homozygous for I148M PNPLA3. Therefore, we aimed to investigate the synergic impact of the 3 at-risk variants on liver injury and hepatocellular carcinoma (HCC) in a large cohort of NAFLD patients, and create in vitro models of genetic NAFLD by silencing TM6SF2 in both HepG2 and MBOAT7 cells.

Low Lipoprotein(a) Levels Predict Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

Dyslipidemia and cardiovascular complications are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis up to hepatocellular carcinoma. Lipoprotein(a) (Lp(a)) has been associated with cardiovascular risk and metabolic abnormalities, but its impact on the severity of liver damage in patients with NAFLD remains to be clarified. Circulating Lp(a) levels were assessed in 600 patients with biopsy-proven NAFLD.

α-Lipoic Acid Improves Hepatic Metabolic Dysfunctions in Acute Intermittent Porphyria: A Proof-of-Concept Study.

Background: Acute intermittent porphyria (AIP) is caused by the haploinsufficiency of porphobilinogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting, and alterations in glucose metabolism, insulin resistance, and mitochondrial turnover may be involved in AIP pathophysiology. Therefore, we investigated the metabolic pathways in PBGD-silenced hepatocytes and assessed the efficacy of an insulin mimic, α-lipoic acid (α-LA), as a potential therapeutic strategy.

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis, thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition.

The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients.

Background And Aims: Dyslipidemia and cardiovascular diseases (CVD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 gene cluster, has been associated CVD, but its impact on metabolic traits and on the severity liver damage in NAFLD has not been investigated yet.

Methods: We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 had HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC), and in 366 HCC samples from The Cancer Genome Atlas (TCGA).

The KLB rs17618244 gene variant is associated with fibrosing MAFLD by promoting hepatic stellate cell activation.

Background: The rs17618244 G>A β-Klotho (KLB) variant has been associated with increased risk of ballooning and inflammation in pediatric patients with metabolic associated fatty liver disease (MAFLD), by reducing KLB expression. In hepatocytes, KLB downregulation induced fat accumulation and the expression of inflammatory and lipotoxic genes. We aimed to examine firstly the impact of the KLB rs17618244 variation on liver damage in adult patients with MAFLD and secondly its effect on hepatic stellate cells (HSCs) activation.

Nonalcoholic fatty liver disease or metabolic dysfunction-associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches.

Background: A consensus of experts has proposed to replace the term nonalcoholic fatty liver disease (NAFLD), whose global prevalence is 25%, with metabolic dysfunction-associated fatty liver disease (MAFLD), to describe more appropriately the liver disease related to metabolic derangements. MAFLD is closely intertwined with type 2 diabetes, obesity, dyslipidaemia, all linked to a rise in the risk of cardiovascular disease (CVDs). Since controversy still stands on whether or not NAFLD/MAFLD raises the odds of CVD, the present review aims to evaluate the impact of NAFLD/MAFLD aetiologies on CV health and the potential correction by dietary and drug approaches.

Mitochondrial dynamics and nonalcoholic fatty liver disease (NAFLD): new perspectives for a fairy-tale ending?

Nonalcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver dysfunctions and it is predicted to become the primary cause of liver failure and hepatocellular carcinoma. Mitochondria are highly dynamic organelles involved in multiple metabolic/bioenergetic pathways in the liver. Emerging evidence outlined that hepatic mitochondria adapt in number and functionality in response to external cues, as high caloric intake and obesity, by modulating mitochondrial biogenesis, and maladaptive mitochondrial response has been described from the early stages of NAFLD.