In the LDLR-/- mouse model we have demonstrated that pharmacological inhibition of ceramide biosynthesis (i) reduces hepatic levels of toxic ceramide species, (ii) reduces plasma ceramides and SM involved in atherosclerosis, (iii) reduces plasma triglycerides, and total cholesterol, (iv) reduces ApoB but increases plasma ApoAI levels leading to a reduced ApoB/ApoAI ratio, (v) improves insulin sensitivity, (vi) reduces hepatic fat and cholesterol accumulation, inflammation and fibrosis and (vii) improves atherosclerosis. Here, INS is linked to atherosclerosis.