Too Much of a Good Thing? An Evolutionary Theory to Explain the Role of Ceramides in NAFLD

Abstract

Non-alcoholic fatty liver disease (NAFLD), which ranges from the relatively benign and reversible fatty liver (NAFL) to the more advanced and deadly steatohepatitis (NASH), affects a remarkably high percentage of adults in the population. Depending upon severity, NAFLD can increase one's risk for diabetes, cardiovascular disease, and hepatocellular carcinoma. Though the dominant histological feature of all forms of the disease is the accumulation of liver triglycerides, these molecules are likely not pathogenic, but rather serve to protect the liver from the damaging consequences of overnutrition. We propose herein that the less abundant ceramides, through evolutionarily-conserved actions intended to help organisms adapt to nutrient excess, drive the cellular events that define NAFL/NASH. In early stages of the disease process, they promote lipid uptake and storage, whilst inhibiting utilization of glucose. In later stages, they stimulate hepatocyte apoptosis and fibrosis. In rodents, blocking ceramide synthesis ameliorates all stages of NAFLD. In humans, serum and liver ceramides correlate with the severity of NAFLD and its comorbidities diabetes and heart disease. These studies identify key roles for ceramides in these hepatic manifestations of the metabolic syndrome.

Keywords: NAFL; NAFLD (non alcoholic fatty liver disease); NASH; ceramide; fatty liver.

Figure 1

Mechanisms of ceramides contribute to NALF and NASH/fibrosis. (A) In NAFL, ceramides promote lipid accumulation ultimately resulting in hepatosteatosis. In promoting steatosis, ceramides stimulate the translocation of CD36 to its active site on the plasma membrane via obligate intermediate PKCζ where it facilitates uptake and esterification of free fatty acids. Ceramide action on PKCζ also upregulates transcription of Srebpc1 and inhibits Akt. Ceramides also reduce mitochondrial efficiency, promoting fat as a preferred substrate. (B) Ceramides promote fibrosis through TGF-β signaling, CREB3L1 proteolysis, stellate cell activation, and hepatocellular apoptosis. Srebpc1, sterol regulatory element binding protein 1; S1P/S2P, site 1 protease, site 2 protease; TM4SF20, transmembrane 4 super family 20; CREB3L1, CAMP responsive element binding protein 3. Figure was created with BioRender.com.

Figure 2

Pharmacological inhibition of de novo ceramide synthesis prevents high fat diet (HFD) induced NASH. (A) Simplified schematic of ceramide de novo synthesis pathway, demonstrating the target of Myriocin (in red). (B) Graphical summary of the beneficial effects of Myriocin treatment in HFD-fed Sprague-Dawley rats. HFD-induced NAFLD related effects are shown in black with the beneficial effects of Myriocin treatments shown with red lines. Figure was created with BioRender.com.