Olufunto O. Badmus

Mechanisms underlying the future development of CVD in mothers with GDM were investigated using a mouse model of GDM that mimics the condition observed in human GDM. Examining the aorta in the later life of the GDM model reveals increased arterial stiffness and endothelin activation associated with vascular remodeling. In addition, kinome analysis reveals suppressed cardiac NO/cGMP/PRKG and impaired AMPK-SIRT1 signaling pathways, which corroborate the impaired ventricular relaxation observed in later life in GDM mothers.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly associated with the development of cardiovascular disease (CVD); however, the mechanisms responsible are currently unknown. We have developed a model of MASLD due to the loss of hepatocyte peroxisome proliferator-activated receptor α (PPARα^HEPKO). We found that plasma beta-hydroxybutyrate (BHOB) levels were significantly reduced in PPARα^HEPKO mice and aimed to investigate the therapeutic potential of restoring BHOB levels in the development of CVD in these mice. Thirty-week-old PPARα^HEPKO and control PPARα^FL/FL mice were randomized to receive 1,3 butanediol (1,3-BDO), a precursor of BHOB, in drinking water for 6 weeks. 1,3-BDO treatment resulted in a significant increase in plasma BHOB levels, a significant decrease in mean arterial blood pressure, improvement in systolic and diastolic function, a decrease in vascular stiffness, and improved exercise performance in PPARα^HEPKO mice. 1,3-BDO treatment did not alleviate hepatic steatosis in PPARα^HEPKO mice; however, it improved plasma cholesterol levels and decreased cardiac lipid accumulation, fibrosis, and apoptosis. 1,3-BDO treatment also resulted in a significant increase in cardiac AMP-activated protein kinase (AMPK) levels. Increasing plasma BHOB levels reverses CVD in our mouse model of MASLD. A similar approach could be an effective strategy for preventing the development of CVD in patients with human MASLD.

Chronic d-galactose (d-gal) treatment is a model to induce accelerated aging-like phenotypes in rodents. However, the sex differences in behavioral and musculoskeletal manifestations of this model are not well understood. Heme oxygenase-1 (HO-1) is a cytoprotective protein that may have anti-aging properties. The goal of this study was to better understand the sex differences in the behavioral and musculoskeletal effects of chronic d-gal treatment in C57BL/6J mice, as well as the role of HO-1 induction or inhibition. Eight-week-old male and female mice received daily saline or d-gal injections (500 mg/kg, s.c.) for 12 weeks. After this time, mice in the d-gal group were randomized into three groups (n = 6/group/sex): d-gal, d-gal + cobalt protoporphyrin (CoPP) (5 mg/kg, s.c. weekly), and d-gal + zinc deutroporphyrin bisglycol (ZnBG) (42 mg/kg, i.p. triweekly) for a period of 4 weeks. Open-field, novel-object recognition, Barnes maze, grip strength, micro-computed tomography (µ-CT), histology, and protein analysis were performed. Chronic d-gal treatment resulted in a sexual dimorphic response, with female mice being more prone to develop deficits in both short- and long-term spatial memory as well as in non-spatial memory. Male mice exhibited deficits only in long-term spatial memory when treated chronically with d-gal. Inhibition of HO-1 was protective in both females and males. Chronic d-gal treatment did not accelerate the development of osteoporosis or sarcopenia in either males or females. Our results demonstrate a sexual dimorphic response to the chronic effects of d-gal treatment on aging, with greater effects in females than in males, which is dependent on HO-1.

Sex differences are a complex and crucial variable in developing and progressing metabolic and cardiovascular disease pathophysiology and clinical outcomes. The female sex, compared to the male sex, is protected from metabolic disturbances and their resulting cardiovascular events. However, the peculiar life phases associated with females, such as puberty, pregnancy, and premenopausal and menopausal stages, are all associated with different risks for the development of cardiovascular disease (CVD). Metabolic dysfunction-associated steatotic liver disease (MASLD), a condition of hepatic steatosis, and at least one feature of metabolic syndrome is associated with an increased risk of cardiovascular events. The risk of MASLD and its progression to the development of CVD differs between men and women. Differences in several factors, including formyl peptide receptor (FPR) 2, adipose tissue distribution, liver pyruvate kinase (LPK), and ketone body production, may underlie the sex differences in the risk of development of MASLD-induced CVD. Understanding the specific risk factors involved in the development and progression of MASLD between the sexes is crucial. This knowledge will provide important insights into the mechanisms responsible for its cardiovascular complications and can potentially lead to therapeutics targeted explicitly for each sex, offering new hope in the fight against MASLD-induced CVD.

The leading cause of death among patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) is cardiovascular disease. A significant percentage of MASLD patients develop heart failure driven by functional and structural alterations in the heart. Previously, we observed cardiac dysfunction in hepatocyte‐specific peroxisome proliferator‐activated receptor alpha knockout (Ppara^HepKO), a mouse model that exhibits hepatic steatosis independent of obesity and insulin resistance. The goal of the present study was to determine mechanisms that underlie hepatic steatosis‐induced cardiac dysfunction in Ppara^HepKO mice. Experiments were performed in 30‐week‐old Ppara^HepKO and littermate control mice fed regular chow. We observed decreased cardiomyocyte contractility (0.17 ± 0.02 vs. 0.24 ± 0.02 μm, p < 0.05), increased cardiac triglyceride content (0.96 ± 0.13 vs. 0.68 ± 0.06 mM, p < 0.05), collagen type 1 (4.65 ± 0.25 vs. 0.31 ± 0.01 AU, p < 0.001), and collagen type 3 deposition (1.32 ± 0.46 vs. 0.05 ± 0.03 AU, p < 0.05). These changes were associated with increased apoptosis as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining (30.9 ± 4.7 vs. 13.1 ± 0.8%, p < 0.006) and western blots showing increased cleaved caspase‐3 (0.27 ± 0.006 vs. 0.08 ± 0.01 AU, p < 0.003) and pro‐caspase‐3 (5.4 ± 1.5 vs. 0.5 ± 0.3 AU, p < 0.02), B‐cell lymphoma protein 2‐associated X (0.68 ± 0.07 vs. 0.04 ± 0.04 AU, p < 0.001), and reduced B‐cell lymphoma protein 2 (0.29 ± 0.01 vs. 1.47 ± 0.54 AU, p < 0.05). We further observed elevated circulating natriuretic peptides and exercise intolerance in Ppara^HepKO mice when compared to controls. Our data demonstrated that lipotoxicity, and fibrosis underlie cardiac dysfunction in MASLD.

Several population studies have observed lower serum bilirubin levels in patients with non-alcoholic fatty liver disease (NAFLD). Yet, treatments to target this metabolic phenotype have not been explored. Therefore, we designed an N-Acetylgalactosamine (GalNAc) labeled RNAi to target the enzyme that clears bilirubin from the blood, the UGT1A1 glucuronyl enzyme (GNUR). In this study, male C57BL/6J mice were fed a high-fat diet (HFD, 60%) for 30 weeks to induce NAFLD and were treated subcutaneously with GNUR or sham (CTRL) once weekly for six weeks while continuing the HFD. The results show that GNUR treatments significantly raised plasma bilirubin levels and reduced plasma levels of the bilirubin catabolized product, urobilin. We show that GNUR decreased liver fat content and ceramide production via lipidomics and lowered fasting blood glucose and insulin levels. We performed extensive kinase activity analyses using our PamGene PamStation kinome technology and found a reorganization of the kinase pathways and a significant decrease in inflammatory mediators with GNUR versus CTRL treatments. These results demonstrate that GNUR increases plasma bilirubin and reduces plasma urobilin, reducing NAFLD and inflammation and improving overall liver health. These data indicate that UGT1A1 antagonism might serve as a treatment for NAFLD and may improve obesity-associated comorbidities.