👤 Michael Downes

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious chronic liver disease with limited therapeutic options. Fibroblast growth factor (FGF) analogs show promising therapeutic benefits for MASLD, yet the underlying mechanisms remain incompletely understood. Here, we studied the mechanism underlying the anti-steatotic properties of FGF1, the prototype member of the FGF family. The effect of FGF1 was studied in human and rodent hepatocytes and in obese mouse models exhibiting acute or chronic endoplasmic reticulum (ER) stress characteristic of MASLD. Metabolic analysis and proteomics were applied to evaluate liver physiology, ER stress and signaling. We show that FGF1 reduces hepatic triglyceride (TG) levels in obese mice (51%, These results define ER stress-dependent modulation of VLDL secretion as a mechanism underlying the anti-steatotic activity of FGF1. Targeting the FGF-UPR pathway may thus have therapeutic potential for treating MASLD. Fibroblast growth factors show therapeutic potential in both preclinical models and clinical trials for treating metabolic dysfunction-associated steatotic liver disease, a highly prevalent condition with limited treatment options. Identifying the mechanisms underlying their anti-steatotic effects may accelerate clinical development. Our finding that triglyceride secretion is the major driver of the anti-steatotic action of FGF1, together with the involvement of an adaptive unfolded protein response, provides deeper insight into the therapeutic potential of this pathway. These results also highlight possible implications for liver physiology and for the circulating lipoprotein profile, with relevance for both efficacy and safety considerations. Show less

Familial hypercholesterolaemia (FH) is a hereditary disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) levels, substantially increasing the risk of atherosclerotic cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) targeting therapies, including monoclonal antibodies and small interfering RNA (siRNA) agents, have emerged as effective lipid lowering therapies. To assess the efficacy and safety of PCSK9-targeting therapy on lipid biomarkers and adverse events in patients with FH, compared with placebo on the background of standard lipid-lowering therapy. A systematic review and meta-analysis were conducted, incorporating data from 23 randomised controlled trials involving adult and paediatric FH patients treated with PCSK9 inhibitors (PCSK9i) or siRNA, including alirocumab, bococizumab, evolocumab, tafolecimab and inclisiran. Eligible studies reported changes in LDL-C, apolipoprotein B (ApoB), lipoprotein a (Lp(a)), triglycerides (TGL) and adverse effects. Pooled mean differences (MDs) and ORs with 95% CIs were calculated using random-effects models, and heterogeneity was assessed with I² statistic. This meta-analysis was registered on PROSPERO (CRD42025631510). A total of 4282 patients were included. PCSK9-targeting therapies significantly reduced LDL-C levels compared with control therapies (MD=-46.64%; 95% CI -50.77% to -42.52%; p<0.00001) and TGL (MD=-15.18%; 95% CI -19.34% to -11.03%; p<0.00001). Significant reductions were also observed for ApoB (MD=-34.94%; 95% CI -40.89% to -28.99%; p<0.00001) and Lp(a) (MD=-22.7%; 95% CI -25.95% to -19.44%; p<0.00001). LDL-C, TGL and ApoB reduction were more significant in heterozygous FH patients than in homozygous patients. The safety profile of these therapies was favourable, with adverse event rates comparable to those of the controls. PCSK9i and Inclisiran demonstrate significant and sustained reductions in LDL-C, ApoB, Lp(a) and TGL in FH patients, especially in heterozygous FH patients. These agents are generally well-tolerated and represent effective treatment options for FH patients inadequately controlled by standard lipid-lowering therapies. Show less

To describe the prevalence and clinicopathologic associations of FGFR-altered urinary tract carcinomas in institutions incorporating reflex testing. Next-generation sequencing was prospectively performed on urinary tract carcinomas for the detection of FGFR1-4 alterations at 2 tertiary care centers (2021-2025), using the Oncomine Comprehensive Assay (OCA) v3 DNA and OCA Plus RNA. Reflex testing was conducted on metastatic and/or advanced (pT3/4) carcinomas. The cohort included 366 patients (239 lower tract carcinomas, 72 upper tract carcinomas, and 55 metastases). Median age was 72.5 years (range, 36-97). Fifty-nine (16.1%) tumors were FGFR-altered. Forty-nine (13.4%) patients with actionable FGFR alterations (33 FGFR3 mutations, 13 FGFR3 fusions, and 3 FGFR2 mutations) were all 55 years or older (P = .097). The prevalence of actionable FGFR alterations was significantly higher in upper vs lower tract carcinomas (23.8% vs 13.8%, P = .007) and in lung metastases vs other metastatic sites (57.1% vs 10.4%, P = .002). A higher frequency was also seen in metastases vs primary tumors (16.4% vs 12.9%), although this difference did not reach statistical significance (P = .482). Actionable FGFR alterations were observed in urothelial carcinoma not otherwise specified (40/261) and in urothelial carcinoma with squamous differentiation (6/43), micropapillary features (2/11), or nested features (2/7). The detection rate for FGFR1-4 alterations in a real-world, dual-institution cohort of urinary tract carcinomas was reported. Show less

Obesity is the principal driver of insulin resistance, and lipodystrophy is also linked with insulin resistance, emphasizing the vital role of adipose tissue in glucose homeostasis. The quality of adipose tissue expansion is a critical determinant of insulin resistance predisposition, with individuals suffering from metabolic unhealthy adipose expansion exhibiting greater risk. Adipocytes are pivotal in orchestrating metabolic adjustments in response to nutrient intake and cell intrinsic factors that positively regulate these adjustments are key to prevent Type-2 diabetes. Employing unique genetic mouse models, we established the critical involvement of heparan sulfate (HS), a fundamental element of the adipocyte glycocalyx, in upholding glucose homeostasis during dietary stress. Genetic models that compromise adipocyte HS accelerate the development of high-fat diet-induced hyperglycemia and insulin resistance, independent of weight gain. Mechanistically, we show that perturbations in adipocyte HS disrupts endogenous FGF1 signaling, a key nutrient-sensitive effector. Furthermore, compromising adipocyte HS composition detrimentally impacts FGF1-FGFR1-mediated endocrinization, with no significant improvement observed in glucose homeostasis. Our data establish adipocyte HS composition as a determinant of Type 2 diabetes susceptibility and the critical dependency of the endogenous adipocyte FGF1 metabolic pathway on HS. Show less