Biology subjects

Sowton, A. P.

Publications and source records attributed to Sowton, A. P..

3 recordsLinked to original sources

bioRxiv2026

Hepatic HIF2α modulates extra-hepatic disease-associated phenotypes during metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) afflicts more than one-third of adults globally, contributing significantly to an increased cardiovascular disease risk. Further, patients with severe liver disease experience muscle weakness (sarcopenic obesity) and fatigue. Hypoxia-inducible factor 2 (HIF2) accumulates in the livers of MASLD patients and has been implicated in disease progression. Here we sought to understand the role of hepatic HIF2 in mediating hepatic and extra-hepatic features of MASLD. Using a well-validated obese mouse model of MASLD, we investigated the impact of hepatocyte-specific HIF2 deletion (hHIF2-/-) on hepatic, cardiac and skeletal muscle metabolism, and cardiac function. Over 28 weeks, mice were exposed to a high-fat, high-fructose, high-cholesterol (GAN) diet, which induced obesity alongside hepatic steatosis, fibrosis and inflammation. In contrast to observations in lean mouse models of liver disease, hHIF2-/- did not protect against MASLD, despite greater hepatic NADH-supported mitochondrial respiration and higher intracellular sphingomyelin levels. Instead, in the hearts of GAN-fed mice, hHIF2-/- caused diacylglycerol accumulation independent of diet, accumulation of long-chain acyl-carnitines and exacerbation of ceramide accumulation. Langendorff-perfused hearts from hHIF2-/- mice showed systolic and diastolic dysfunction, including 24% lower left ventricular developed pressure and 34% lower maximal rate of relaxation (dP/dtmin). However, isolated hearts from hHIF2-/- mice were protected against MASLD-associated sympathetic dominance, determined using autonomic receptor agonist stimulation. Both GAN-feeding and hHIF2-/- were associated with lower lean mass (14% and 5.4% lower than respective controls), whilst hHIF2-/- enhanced OXPHOS-associated protein levels in gastrocnemius muscle. Overall, hHIF2-/- resulted in detrimental extra-hepatic effects, including myocardial lipid accumulation, impaired cardiac function, and loss of whole-body lean mass, with no apparent protection against MASLD disease progression.

physiology↗

bioRxiv2024

Chronic inorganic nitrate supplementation does not improve metabolic health and worsens disease progression in mice with diet-induced obesity.

Inorganic nitrate (NO3-) has been proposed to be of therapeutic use as a dietary supplement in obesity and related conditions including the Metabolic Syndrome (MetS), type-II diabetes and metabolic dysfunction associated steatotic liver disease (MASLD). Administration of NO3- to endothelial nitric oxide synthase-deficient mice reversed aspects of MetS, however the impact of NO3- supplementation in diet-induced obesity is not well understood. Here we investigated the whole-body metabolic phenotype and cardiac and hepatic metabolism in mice fed a high-fat high-sucrose (HFHS) diet for up to 12-months of age, supplemented with 1 mM NaNO3 (or NaCl) in their drinking water. HFHS-feeding was associated with a progressive obesogenic and diabetogenic phenotype, which was not ameliorated by NO3-. Furthermore, HFHS-fed mice supplemented with NO3- showed elevated levels of cardiac fibrosis, and accelerated progression of MASLD including development of hepatocellular carcinoma in comparison with NaCl-supplemented mice. NO3- did not enhance mitochondrial {beta}-oxidation capacity in any tissue assayed and did not suppress hepatic lipid accumulation, suggesting it does not prevent lipotoxicity. We conclude that NO3- is ineffective in preventing the metabolic consequences of an obesogenic diet and may instead be detrimental to metabolic health against the background of HFHS-feeding. This is the first report of an unfavorable effect of long-term nitrate supplementation in the context of the metabolic challenges of overfeeding, warranting urgent further investigation into the mechanism of this interaction. New & NoteworthyInorganic nitrate has been suggested to be of therapeutic benefit in obesity-related conditions as it increases nitric oxide bioavailability, enhances mitochondrial {beta}-oxidation and reverses Metabolic Syndrome in eNOS-/- mice. However, we here show that over 12 months, nitrate was ineffective in preventing metabolic consequences in high-fat high-sucrose fed mice, and worsened aspects of metabolic health, impairing cholesterol handling, increasing cardiac fibrosis, and exacerbating steatotic liver disease progression, with acceleration to hepatocellular carcinoma.

physiology↗

bioRxiv2022

Oxygen is a critical regulator of cellular metabolism and function in cell culture

Cell culture is generally considered to be hyperoxic. However, the importance of cellular oxygen consumption is often underappreciated, with rates of oxygen consumption often sufficient to cause hypoxia at cell monolayers. We initially focused on cultured adipocytes as a terminally differentiated cell-type with substantial oxygen consumption rates to support diverse cellular functions. Under standard conditions, cultured adipocytes are hypoxic and highly glycolytic. Increasing oxygen diverted glucose flux toward mitochondria and resulted in thousands of gene expression changes that pointed toward alleviated physiological transcriptional responses to hypoxia. Phenotypically, providing more oxygen increased adipokine secretion and rendered adipocytes more sensitive to insulin and lipolytic stimuli. The functional benefits of increasing pericellular oxygen were transferable to other cellular systems including hPSC-derived hepatocytes and cardiac organoids. Our findings suggest that oxygen is limiting in many terminally-differentiated cell culture systems, and that controlling oxygen availability can improve the quality and translatability of cell models.

cell biology↗