Plasma lipids are maintained within a narrow physiologic range and exhibit circadian rhythmicity. Plasma triglyceride and cholesterol levels were high in the night due to changes in apolipoprotein B-lipoproteins in ad libitum fed rats and mice maintained in a 12-h photoperiod. Absorption of [ 3 H]triolein or [ 3 H]cholesterol was higher at 2400 h than at 1200 h, indicating that intestinal lipoprotein production shows diurnal variation. Moreover, intestinal microsomal triglyceride transfer protein (MTP) activity, protein, mRNA, and gene transcription showed diurnal variations and were high at 2400 h. Similar to the small intestine, hepatic MTP activity, protein, and mRNA levels also changed significantly within a day. MTP was induced in fasted animals soon after refeeding. When mice were subjected to restricted feeding, MTP expression was high at the expected time of food availability. In contrast, extended exposures to light and dark completely abolished rhythmicity in MTP expression and plasma lipid levels. These studies show that MTP expression and plasma lipid undergo diurnal regulation and exhibit peaks and nadirs at similar times and suggest that diurnal modulation of MTP is a major determinant of daily changes in plasma lipids. Furthermore, environmental factors, such as food and light, play an important role in MTP regulation.Circadian rhythm is a repetitive occurrence of physiological processes with an approximate interval of 24 h. Several biochemical, physiological, and pathological processes exhibit circadian rhythms. Plasma lipid concentrations are maintained within a narrow range and exhibit circadian rhythmicity in humans and rodents (1-4). Plasma lipid homeostasis is maintained by balancing lipoprotein production and catabolism. Lipoprotein production is critically dependent on apolipoprotein B (apoB) 2 and microsomal triglyceride transfer protein (MTP) (5-8). ApoB is a structural protein required for the assembly of lipoproteins, whereas MTP is an essential chaperone for their assembly (5, 6, 9). MTP is a heterodimeric protein of 97-and 55-kDa polypeptides mainly present in the endoplasmic reticulum of hepatocytes and enterocytes (5,6,8,10). It is crucial for the first step of lipoprotein assembly, because it transfers lipids and binds to apoB (5, 11). Via these mechanisms, MTP is believed to avoid improper folding and premature degradation of apoB. A vital role of MTP in the formation and secretion of apoB is supported by the fact that patients with abetalipoproteinemia, a disorder caused by mutations in the mttp gene that codes for the 97-kDa subunit of MTP, have no apoB in the plasma (12, 13). Molecular identification of MTP as a key chaperone for lipoprotein assembly provided a novel opportunity to determine the mechanisms that control its regulation. Intestinal and liver MTP is regulated by dietary fats (14, 15), hormones such as insulin and leptin, (16), transcription factors such as HNF4 (17-19), peroxisome proliferator-activated receptor ␣ (20), and development (21-23). In addition, geneti...