AMP-activated kinase (AMPK) regulates multiple signaling pathways involved in glucose and lipid metabolism in response to changes in hormonal and nutrient status. Cell culture studies have shown that AMPK phosphorylation and inhibition of the rate-limiting enzyme in the mevalonate pathway - HMG-CoA-Reductase (HMGCR) at Ser871 (human HMGCR Ser872) suppresses cholesterol synthesis. In order to evaluate the role of AMPK-HMGCR signaling in vivo we generated mice with a Ser871Ala knock-in mutation (HMGCR KI). Cholesterol synthesis was significantly suppressed in WT but not in HMGCR KI hepatocytes in response to AMPK activators. Consistently, liver cholesterol synthesis and cholesterol levels were significantly up-regulated in HMGCR KI mice, resulting in increased plaque size when crossed onto atherosclerosis-prone background. When fed a high carbohydrate diet HMGCR KI mice had enhanced triglyceride synthesis and liver steatosis resulting in impaired glucose homeostasis. Our results demonstrate that AMPK-HMGCR signaling alone is sufficient to regulate both cholesterol and triglyceride synthesis under conditions of a high carbohydrate diet. These findings highlight the tight coupling between the mevalonate and fatty acid synthesis pathways as well as revealing a role of AMPK in suppressing the deleterious effects of a high carbohydrate diet.