Lipid alterations in chronic liver disease and liver cancer. JHEP reports : innovation in hepatology Lipids are a complex and diverse group of molecules with crucial roles in many physiological processes, as well as in the onset, progression, and maintenance of cancers. Fatty acids and cholesterol are the building blocks of lipids, orchestrating these crucial metabolic processes. In the liver, lipid alterations are prevalent as a cause and consequence of chronic hepatitis B and C virus infections, alcoholic hepatitis, and non-alcoholic fatty liver disease and steatohepatitis. Recent developments in lipidomics have also revealed that dynamic changes in triacylglycerols, phospholipids, sphingolipids, ceramides, fatty acids, and cholesterol are involved in the development and progression of primary liver cancer. Accordingly, the transcriptional landscape of lipid metabolism suggests a carcinogenic role of increasing fatty acids and sterol synthesis. However, limited mechanistic insights into the complex nature of the hepatic lipidome have so far hindered the development of effective therapies. 10.1016/j.jhepr.2022.100479

Steatotic liver disease. Lancet (London, England) Steatotic liver disease is the overarching term for conditions characterised by abnormal lipid accumulation in the liver (liver or hepatic steatosis). Steatotic liver disease encompasses what was previously termed non-alcoholic fatty liver disease (NAFLD), which is now called metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, steatotic liver disease includes alcohol-related liver disease (ALD) and MetALD, the new classification for the overlap between MASLD and ALD, and rare causes of liver steatosis. Cirrhosis is globally the 11th leading cause of death, and steatotic liver disease has become the leading cause of cirrhosis in the EU and USA. Steatotic liver disease affects around 30% of the global population and is mainly driven by obesity, type 2 diabetes, and alcohol intake, but only a minor proportion with steatotic liver disease progress to cirrhosis. The presence and progression of liver fibrosis led by hepatic inflammation is the main predictor of liver-related death across the entire spectrum of steatotic liver diseases. A combination of recent advancements of widely available biomarkers for early detection of liver fibrosis together with considerable advancements in therapeutic interventions offer the possibility to reduce morbidity and mortality in patients with steatotic liver disease. This Seminar covers the recent reclassification of steatotic liver disease and how it reflects clinical practice and prognosis. For early detection of liver fibrosis, we propose a collaborative diagnostic framework between primary care and liver specialists. Lastly, we discuss current best practices for managing steatotic liver disease, we explore therapeutic targets across the spectrum of steatotic liver diseases, and we review the pipeline of drugs in development for MASLD. 10.1016/S0140-6736(24)01811-7

Lipid metabolism in MASLD and MASH: From mechanism to the clinic. JHEP reports : innovation in hepatology Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is recognised as a metabolic disease characterised by excess intrahepatic lipid accumulation due to lipid overflow and synthesis, alongside impaired oxidation and/or export of these lipids. But where do these lipids come from? The main pathways related to hepatic lipid accumulation are lipogenesis and excess fatty acid transport to the liver (due to increased lipolysis, adipose tissue insulin resistance, as well as excess dietary fatty acid intake, in particular of saturated fatty acids). Not only triglycerides but also other lipids are secreted by the liver and are associated with a worse histological profile in MASH, as shown by lipidomics. Herein, we review the role of lipid metabolism in MASLD/MASH and discuss the impact of weight loss (diet, bariatric surgery, GLP-1RAs) or other pharmacological treatments (PPAR or THRβ agonists) on hepatic lipid metabolism, lipidomics, and the resolution of MASH. 10.1016/j.jhepr.2024.101185

Lipid Metabolism in Metabolic-Associated Steatotic Liver Disease (MASLD). Metabolites Metabolic-associated steatotic liver disease (MASLD) is a cluster of pathological conditions primarily developed due to the accumulation of ectopic fat in the hepatocytes. During the severe form of the disease, i.e., metabolic-associated steatohepatitis (MASH), accumulated lipids promote lipotoxicity, resulting in cellular inflammation, oxidative stress, and hepatocellular ballooning. If left untreated, the advanced form of the disease progresses to fibrosis of the tissue, resulting in irreversible hepatic cirrhosis or the development of hepatocellular carcinoma. Although numerous mechanisms have been identified as significant contributors to the development and advancement of MASLD, altered lipid metabolism continues to stand out as a major factor contributing to the disease. This paper briefly discusses the dysregulation in lipid metabolism during various stages of MASLD. 10.3390/metabo14010012