The Lard Works in Mysterious Ways: Ceramides in Nutrition-Linked Chronic Disease

Abstract

Diet influences onset, progression, and severity of several chronic diseases, including heart failure, diabetes, steatohepatitis, and a subset of cancers. The prevalence and clinical burden of these obesity-linked diseases has risen over the past two decades. These metabolic disorders are driven by ectopic lipid deposition in tissues not suited for fat storage, leading to lipotoxic disruption of cell function and survival. Sphingolipids such as ceramides are among the most deleterious and bioactive metabolites that accrue, as they participate in selective insulin resistance, dyslipidemia, oxidative stress and apoptosis. This review discusses our current understanding of biochemical pathways controlling ceramide synthesis, production and action; influences of diet on ceramide levels; application of circulating ceramides as clinical biomarkers of metabolic disease; and molecular mechanisms linking ceramides to altered metabolism and survival of cells. Development of nutritional or pharmacological strategies to lower ceramides could have therapeutic value in a wide range of prevalent diseases. Expected final online publication date for the Annual Review of Nutrition, Volume 42 is August 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Effect of an eight-week high-intensity interval training programme on circulating sphingolipid levels in middle-aged adults at elevated cardiometabolic risk (SphingoFIT)—Protocol for a randomised controlled exercise trial

“…Primarily in muscle and liver cells, sphingolipids accumulate as ceramides, a particular subclass of sphingolipids [ 10 ]. Initially, this pathological ceramide accumulation 1) reduces the translocation of glucose transporters to the cell membrane, 2) improves fatty acid storage and uptake, and 3) impairs mitochondrial efficiency, resulting in the production of reactive oxygen species [ 12 ]. This initial phase of metabolism alteration leads to peripheral insulin resistance and NAFLD [ 11 , 12 ].…”

“…Initially, this pathological ceramide accumulation 1) reduces the translocation of glucose transporters to the cell membrane, 2) improves fatty acid storage and uptake, and 3) impairs mitochondrial efficiency, resulting in the production of reactive oxygen species [ 12 ]. This initial phase of metabolism alteration leads to peripheral insulin resistance and NAFLD [ 11 , 12 ]. Failure to manage this sphingolipid overload results in lipotoxicity, a phenomenon characterised by apoptosis and fibrosis, which leads to CAD, non-alcoholic steatohepatitis (NASH), or T2DM [ 11 , 12 ].…”

“…This initial phase of metabolism alteration leads to peripheral insulin resistance and NAFLD [ 11 , 12 ]. Failure to manage this sphingolipid overload results in lipotoxicity, a phenomenon characterised by apoptosis and fibrosis, which leads to CAD, non-alcoholic steatohepatitis (NASH), or T2DM [ 11 , 12 ]. Lastly, ceramides in excess are also carried on LDL, where they drive LDL transcytosis through the endothelium and uptake into macrophages [ 13 , 14 ].…”

“…Blue boxes highlight pathophysiological changes and related clinical conditions. This figure is based on [ 12 , 17 ].…”

High‐fat high‐sucrose diet‐induced skeletal muscle insulin resistance in female rats: a new soprano in the DAG chorus

“…For decades, the role of lipid moieties – the most discussed being diacylglycerols (DAGs) and ceramides – in causing diet‐induced insulin resistance has been debated (Nicholson et al., 2022; Petersen & Shulman, 2018). In a recent edition of the Journal of Physiology , Jani et al.…”