The principles guiding the diurnal organization of biological pathways remain to be fully elucidated. Here, we perturb the hepatic transcriptome through nutrient regulators (high-fat diet and mTOR signaling components) to identify enduring properties of pathway organization. Temporal separation and counter-regulation between pathways of energy metabolism and inflammation/proliferation emerge as persistent transcriptome features across animal models, and network analysis identifies the G0s2 and Rgs16 genes as potential mediators at the metabolism-inflammation interface. Mechanistically, G0s2 and Rgs16 are sequentially induced during the light phase, promoting amino acid oxidation and suppressing overall mitochondrial respiration. In their absence, sphingolipids and diacylglycerides accumulate, accompanied by hepatic inflammation and hepatocyte proliferation. Notably, the expression of G0s2 and Rgs16 is further induced in obese mouse livers, and silencing of their expression accentuates hepatic fibrosis. Therefore, diurnal regulation of energy metabolism alleviates inflammatory and proliferative stresses under physiological and pathological conditions.