👤 Simone Bini

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 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

Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) are regulators of triglyceride storage and utilization. Bariatric surgery (BS) leads to profound changes in adipose tissue composition and energy metabolism. We evaluated the impact of BS on plasma levels of ANGPTL3 and ANGPTL4. Twenty-seven subjects affected by morbid obesity with or without type 2 diabetes (T2D) underwent Roux-en-Y gastric bypass (RYGB) and 18 patients with advanced T2D received Biliopancreatic Diversion (BPD). Fasting ANGPTL proteins levels, insulin sensitivity (evaluated by euglycemic hyperinsulinemic clamp), total bile acids (TBA) and free fatty acids (FFA) were measured at baseline and 1 year after surgery. Both surgical procedures resulted in the loss of fat mass, improved glucose control, and a ∼2-fold increase of insulin sensitivity. ANGPTL4 levels decreased significantly with both RYGB (26.6 ± 0.6 to 24.4 ± 0.3 ng/mL, p = 0.001) and BPD (27.9 ± 1.5 to 24.0 ± 0.5 ng/mL, p = 0.003). In contrast, ANGPTL3 concentrations did not change after RYGB but rose following BPD (225 ± 20 to 300 ± 15 ng/mL, p = 0.003). By multiple regression analysis, changes after BS in ANGPTL4 were independently associated with changes in blood glucose, (p = 0.0169) whereas changes in ANGPTL3 were associated with variations in FFA (p = 0.008) and insulin sensitivity (p = 0.043). Circulating ANGPTL4 is reduced by BS, probably due to the loss of fat mass and improved insulin sensitivity. Conversely, ANGPTL3 levels increased after BPD, but not after RYGB, presumably because of the metabolic changes induced by the malabsorptive effect of BPD. Show less

Angiopoietin-like proteins, namely ANGPTL3-4-8, are known as regulators of lipid metabolism. However, recent evidence points towards their involvement in the regulation of adipose tissue function. Alteration of adipose tissue functions (also called adiposopathy) is considered the main inducer of metabolic syndrome (MS) and its related complications. In this review, we intended to analyze available evidence derived from experimental and human investigations highlighting the contribution of ANGPTLs in the regulation of adipocyte metabolism, as well as their potential role in common cardiometabolic alterations associated with adiposopathy. We finally propose a model of ANGPTLs-based adipose tissue dysfunction, possibly linking abnormalities in the angiopoietins to the induction of adiposopathy and its related disorders. Show less