ABSTRACT
Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase 1 (DES1), which normally inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals or tissue-specific deletion in the liver and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or obesogenic diets. Mechanistic studies revealed ceramide actions that promoted lipid uptake and storage and impaired glucose utilization, none of which could be recapitulated by (dihydro)ceramides that lacked the critical double bond. These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and metabolic disorders.
Subject(s)
Ceramides/metabolism , Fatty Liver/genetics , Fatty Liver/metabolism , Insulin Resistance/genetics , Membrane Proteins/genetics , Oxidoreductases/genetics , Animals , Ceramides/chemistry , Ceramides/genetics , Diet, High-Fat/adverse effects , Gene Deletion , Leptin/deficiency , Mice , Mice, Mutant Strains , Sphingolipids/chemistry , Sphingolipids/metabolismABSTRACT
Obesity is a complex metabolic disorder associated with the development of non-communicable diseases such as cirrhosis, non-alcoholic fatty liver disease, and type 2 diabetes. In humans and rodents, obesity promotes hepatic steatosis and inflammation, which leads to increased production of pro-inflammatory cytokines and acute-phase proteins. Liver macrophages (resident as well as recruited) play a significant role in hepatic inflammation and insulin resistance (IR). Interestingly, depletion of hepatic macrophages protects against the development of high-fat-induced steatosis, inflammation, and IR. Kupffer cells (KCs), liver-resident macrophages, are the first-line defense against invading pathogens, clear toxic or immunogenic molecules, and help to maintain the liver in a tolerogenic immune environment. During high fat diet feeding and steatosis, there is an increased number of recruited hepatic macrophages (RHMs) in the liver and activation of KCs to a more inflammatory or M1 state. In this review, we will focus on the role of liver macrophages (KCs and RHMs) during obesity.
