Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.

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-yearold woman with early aggressive NAFLD due to severe hypertriglyceridemia that ensued from a combination of genetic variants and additional metabolic risk factors.Methods: Genetic screening was performed by using whole-exome sequencing (WES), and mitochondrial structures were evaluated by TEM.Results: At presentation, the patient is reported to have hepatomegaly, hypertriglyceridemia, and raised transaminases. Genetic analysis revealed that the patient beard heritable alterations in genes implicated in lipid handling, among which APOB, APOE, CETP, and HSPG2, accompanied by missense mutations in genes involved in mitochondrial function, i.e., AK2, ALG6, ASPA, NDUFAF1, POLG, and TMEM70. Abdominal ultrasound (US) and transient elastography were suggestive of severe hepatic steatosis and fibrosis. A liver biopsy confirmed the diagnosis of non-alcoholic steatohepatitis (NASH)-related fibrosis. Thus, to better outline whether mutations involved in lipid remodeling and mitochondrial function may also affect organelles' morphology, we exploited TEM. Along with multifaceted abnormalities of mitochondrial architecture that have been already observed in patients with NAFLD, astonishing ultrastructural defects, such as mitochondrial vacuolization, sub-compartmentalization, and onion-like mitochondria, were identified.

Nonalcoholic fatty liver disease (NAFLD) onset and its progression towards nonalcoholic steatohepatitis (NASH) features increased intestinal permeability and leaky gut, thereby favoring the escape of endotoxin [lipopolysaccharides (LPS)] from the gut to the liver. The aim of this study was to resemble the crosstalk between intestine and liver during NAFLD by using an in vitro model of co-culture system. Enterocytes (Caco-2) were seeded on Transwell filters (pore size: 0.4 μm) and cultured for 21 days to constitute a confluent monolayer, and then they were co-cultivated with hepatocytes (HepG2) for an additional 24 h. Caco-2 on the apical chamber were exposed to LPS and/or a mixture of palmitic and oleic acid (PAOA) for 24 h. FITC-4000 dextrans (FD4) permeability across Caco-2 monolayer was increased by the treatment of Caco-2 cells with PAOA and LPS, consistently with tight junction-associated proteins reduction. Caco-2 exposure to PAOA/LPS promoted ApoB, triglyceride (TG), and free fatty acid secretion in basolateral media. In turn, HepG2 co-cultured with Caco-2 exposed to LPS, PAOA, or both accumulated lipid droplets and increased intracellular TG content. Likewise, Caco-2 released pro-inflammatory cytokines in basolateral media. These events triggered endoplasmic reticulum (ER) and oxidative stress, enhancing reactive oxygen species (ROS), H2O2, aldehyde derivate production, and ROS-induced DNA damage in HepG2 cells. Hence, Caco-2/HepG2 co-culture system may faithfully reproduce the breach in the intestinal barrier integrity that occurs in NAFLD, thus resulting in the increased inflammatory response and ER and oxidative and stress, which promote the switch towards NASH.

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