👤 Daniele Tramontano

Lifelong APOB gene inactivation lowers LDL-C and cardiovascular risk, but impairs hepatic lipoprotein export, predisposing to chronic liver disease (CLD). The extent to which common steatogenic factors modulate this risk remains unclear. Moreover, the balance between long-term cardiovascular protection and CLD risk in APOB variant carriers has never been evaluated. Using UK Biobank data, we analysed 241 APOB loss-of-function (LoF) carriers and 410 721 non-carriers, stratified by steatogenic risk factors, including age, sex, diabetes, BMI, alcohol intake and the PNPLA3-rs738409 genotype. Associations with transaminase levels, CLD and cardiovascular (ASCVD) outcomes were assessed using Python and R packages. APOB carriers had ~35% lower LDL-C and apoB levels, along with reduced total triglycerides and Lp(a) (all p < 0.001). Baseline ALT and AST were higher in carriers than in non-carriers (P Long-term exposure to low LDL-C levels due to APOB LoF variants has opposite consequences, reducing ASCVD risk but increasing CLD risk, especially in the presence of diabetes and obesity. These findings highlight the importance of balancing cardiovascular benefit with hepatic safety when considering apoB-targeting therapies. Show less

Familial chylomicronemia (FCS) and multifactorial or persistent chylomicronemia syndromes (MCS, pCS) are rare, severe disorders characterized by extreme hypertriglyceridemia and a high risk of recurrent, potentially life-threatening acute pancreatitis. Most patients do not achieve adequate triglyceride control with lifestyle interventions or conventional lipid-lowering therapies, leaving them exposed to persistent complications. This review critically examines emerging therapeutic strategies aimed at improving triglyceride control and reducing acute pancreatitis risk. Advances targeting key molecular regulators of triglyceride metabolism have shown substantial promise. APOC3 inhibitors, including volanesorsen, olezarsen, and plozasiran, achieve up to 80% reductions in triglycerides and markedly lower AP incidence, with favorable safety profiles. ANGPTL3 inhibition via evinacumab may benefit patients with residual lipoprotein lipase activity, including polygenic or mixed chylomicronemia, and could be used during acute sHTG episodes. Lomitapide, acting independently of LPL, is effective in selected FCS patients but requires careful hepatic monitoring. FGF21 analogs, such as pegozafermin, are in early development and show potential for metabolic dysfunction-associated steatotic liver disease, though their impact on acute pancreatitis prevention remains to be established. These emerging mechanism-based therapies are reshaping the management of severe hypertriglyceridemia, offering targeted approaches to reduce triglycerides and acute pancreatitis risk. Ongoing studies will clarify long-term safety, durability of response, and optimal patient selection, providing a framework for improved clinical outcomes. Show less

We aimed to compare the molecular and clinical characteristics of patients identified in Italy as affected by either familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS) and to assess the overall benefit of novel triglyceride-lowering therapies prescribed to these patients within the routine clinical care. From the national LIPIGEN-sHTG (Lipid Transport Disorders Italian Genetic Network-Severe Hypertriglyceridemia) registry, 169 patients (57 FCS, 51 MCS, 61 variant-negative, variant-negative MCS) were retrospectively analyzed. Data on clinical and genetic characteristics, medical history, and medications were collected. Peak triglyceride levels were used to define untreated lipid phenotypes. In FCS, 72% exhibited biallelic As compared with MCS, patients with FCS showed a more severe phenotype and higher prevalence of Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by severe hypertriglyceridemia. It is caused by loss-of-function variants in the genes encoding the lipoprotein lipase (LPL) enzyme and its cofactors, which severely impair the hydrolysis of triglycerides (TG). Its main complication is represented by acute pancreatitis (AP), a potentially life-threatening condition. Conventional TG-lowering therapies are poorly effective in FCS, thus requiring the search of novel treatments. Lomitapide, an inhibitor of microsomal triglyceride transfer protein (MTP), has demonstrated efficacy in reducing TG levels in FCS. However, it is associated with hepatic side effects, namely liver fat accumulation. Here we present a case study of a 71-year-old female patient with genetically confirmed FCS, baseline TG level of 2300 mg/dL (25.97 mmol/L) and a history of AP, who was treated with lomitapide for almost 5 years. The treatment allowed a marked reduction of TG (about 90%) and no recurrence of AP. However, hepatic monitoring during treatment revealed a progressive worsening of liver fat accumulation as detected by magnetic resonance imaging (MRI), which was associated with pronounced increases in liver transaminases and liver stiffness (up to 15 kPa). Due to these hepatic adverse events, it was decided to discontinue therapy with lomitapide. An MRI scan repeated after 70 days of drug withdrawal revealed complete resolution of fatty liver disease associated with normalization of liver stiffness (4.1 kPa) and liver transaminases. This case demonstrates the reversibility of lomitapide-induced fatty liver and underscores the importance of regular monitoring of the liver safety during lomitapide to guide timely interventions. Show less

The epithelial-to-mesenchymal transition (EMT) is a complex transcriptional program induced by transforming growth factor β1 (TGF-β1). Histone lysine-specific demethylase 1 (LSD1) has been recognized as a key mediator of EMT in cancer cells, but the precise mechanism that underlies the activation and repression of EMT genes still remains elusive. Here, we characterized the early events induced by TGF-β1 during EMT initiation and establishment. TGF-β1 triggered, 30-90 min post-treatment, a nuclear oxidative wave throughout the genome, documented by confocal microscopy and mass spectrometry, mediated by LSD1. LSD1 was recruited with phosphorylated SMAD2/3 to the promoters of prototypic genes activated and repressed by TGF-β1. After 90 min, phospho-SMAD2/3 downregulation reduced the complex and LSD1 was then recruited with the newly synthesized SNAI1 and repressors, NCoR1 and HDAC3, to the promoters of TGF-β1-repressed genes such as the Wnt soluble inhibitor factor 1 gene (WIF1), a change that induced a late oxidative burst. However, TGF-β1 early (90 min) repression of transcription also required synchronous signaling by reactive oxygen species and the stress-activated kinase c-Jun N-terminal kinase. These data elucidate the early events elicited by TGF-β1 and the priming role of DNA oxidation that marks TGF-β1-induced and -repressed genes involved in the EMT. Show less