Endocrine Abstracts

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. It represents a spectrum of disease, ranging from steatosis to non-alcoholic steatohepatitis, progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. BAs, as well as their intermediary products (oxysterols), are metabolic modulators exerting their effects through activation of nuclear receptors (NRs), including the farnesoid-X- (FXR) and liver-X-receptors (LXR). Cruciall...

Hepatocellular carcinoma (HCC) is the 6th most common form of cancer and the 4th most common cause of cancer related death. AKR1C1 is a member of the aldo-keto reductase 1C (AKR1C) subfamily and has important roles in steroid hormone metabolism and in reducing lipid peroxides. AKR1C1 is ubiquitously expressed, with high levels of expression in the liver. Studies have identified differential expression in HCC with high levels of AKR1C1 expression associate...

Primary human hepatocytes are considered the ‘gold standard’ to explore metabolic phenotype within the liver, however they come with limitations, such as donor variability, lack of proliferation and rapid phenotype loss. The human hepatoma cell line, HepG2, has been used extensively in cell-based metabolic studies but there are significant limitations including their malignant origin and inherent low rates of triglyceride secretion. The aim of this study was to inves...

Introduction: AKR1D1 is a 5β-reductase that sits at the interface of steroid hormone metabolism and primary bile acid biosynthesis. 5β-reduced androgens are widely believed to be inactive, but to our knowledge there are currently no data that have directly tested their ability to activate the androgen receptor (AR). We therefore wanted to test the ability of AKR1D1 to regulate androgen availability in vitro and to determine if 5β-reduced androgens are a...

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder (UCD) with a prevalence of one in 60-70,000 in humans. It is mainly caused by mutations in the OTC gene, which encodes the enzyme ornithine transcarbamylase. Patients with OTCD present disturbed urea cycle function and ammonia accumulation in the bloodstream, downstream leading to a range of symptoms, including developmental delay, cerebral oedema, coma, and death. We developed a human...

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease ranging from simple intrahepatic lipid accumulation to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). 5β-reductase (AKR1D1) is a liver enzyme that catalyses a fundamental step in bile acid (BA) synthesis. Both BAs and BA intermediates are established as potent regulators of metabolic and proliferative phenotype. We have hypothesised that AKR1D1 plays a crucial role in NAFLD and HCC. Human liver b...

Bile acids (BAs) are synthesised from cholesterol in the liver and promote lipid digestion. An emerging body of evidence, however, suggests that BAs are also key signaling molecules with potent metabolic and endocrine functions, exerting their effects through activation of BA receptors, including the farnesoid-X- (FXR) and the G-protein-coupled- (TGR5) receptors. Disturbed BA synthesis has been associated with type 2 diabetes mellitus and insulin resistance, and recent studies...

The 5-reductases are steroid metabolising enzymes that saturate the C4=C5 bond of the steroid A-ring, and their substrates include androgens, glucocorticoids, and bile acids. 5β-reductases (SRD5A1 & SRD5A2) convert testosterone to the more potent androgen 5β-dihydrotestosterone, and carry out the first step in glucocorticoid clearance, generating 5β-dihydrocortisol from cortisol. 5β-reductase (AKR1D1) is also able to carry out the first step of glucocor...

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease ranging from intrahepatic lipid accumulation to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Liver 5β-reductase (AKR1D1) catalyses a fundamental step in bile acid (BA) synthesis. BAs and BA intermediates are potent regulators of metabolic and proliferative phenotype. We have hypothesised that AKR1D1 plays a crucial role in NAFLD and HCC. Liver biopsies and serum samples were obtained from healt...

Glycogen storage disease 1A (GSD1A) is an inherited metabolic disorder caused by glucose-6-phosphatase (G6PC) deficiency. Patients with GSD1A present disturbed glucose homeostasis and exhibit glycogen accumulation accompanied by hepatomegaly, hypoglycemia, lactic acidosis and hyperlipidemia. However, there are currently no licensed treatments for GSD1A, and human in vitro systems for disease modelling and drug screening are lacking. We aimed to develop a human hepatoc...