Lipogenesis is exquisitely regulated by nutritional/hormonal states. Transcription of fatty acid synthase (FAS), a central enzyme in lipogenesis, is low in fasting but increases drastically with feeding. In transcriptional activation of FAS by feeding/insulin, USF constitutively bound to the −65 E-box is required. Here, we show that USF functions as a molecular switch by recruiting various interacting proteins during the fasting/feeding transition. During feeding/insulin, USF-1 recruits and is phosphorylated by DNA-PK, which is dephosphorylated/activated by PP1. Phosphorylation of USF-1 allows recruitment of and acetylation by P/CAF, resulting in the FAS promoter activation. In fasting, USF-1 is deacetylated by HDAC9 causing the promoter inactivation. DNA break/repair components associated with USF also bring about transient DNA breaks during feeding-induced FAS activation. In DNA-PK deficient SCID mice, feeding induced USF-1 phosphorylation/acetylation, DNA-breaks, and FAS activation leading to lipogenesis are impaired, resulting in decreased liver and circulating triglyceride levels. Our study demonstrates that DNA-PK mediates the feeding/insulin-dependent lipogenic gene activation.

Background The prognostic utility of ankle brachial index (ABI) may be hampered in persons with diabetes due to peripheral arterial stiffening in the ankles. Stiffening of toe arteries occurs infrequently in diabetes. Objectives We aim to determine the nature of the relationship of the toe brachial index (TBI) and ABI with cardiovascular (CVD) mortality, and to determine whether the associations are modified in individuals with diabetes. Methods Individuals with clinically suspected atherosclerotic PAD who underwent ABI and TBI measurements in a vascular laboratory were followed longitudinally for CVD mortality. Results Among 469 (89% men) participants, the mean age was 68 ± 9 years and 36% had diabetes. The mean ABI was 0.83 ± 0.28 and the mean TBI was 0.60 ± 0.24. During 7.0 years (median) follow-up, there were 158 CVD deaths. Association of the ABI categories with CVD events differed in diabetic vs. non-diabetic participants (P-interaction = .002). In contrast, association of the TBI categories with CVD events were similar irrespective of diabetes status (P-interaction = .17). Among diabetic patients, a U-shaped relationship was observed between ABI categories and CVD death; both those with low (< 0.90) and high (> 1.30) ABI were at higher risk than those with normal (0.90–1.30) ABI. In non-diabetic patients, association of ABI categories with CVD death was linear, such that those with ABI > 1.30 were at the lowest risk, whereas those with ABI < 0.90 were at higher risk. In contrast, the association of TBI categories with CVD death was linear irrespective of diabetes status. High TBI categories consistently predicted low risk, whereas risk was higher with progressively lower TBI categories. Conclusions Among diabetic individuals with clinically suspected PAD, both those with low and high ABI are at higher risk of CVD death. In contrast, a linear relationship was observed between TBI categories and CVD death irrespective of diabetes status. These findings suggest that stiffened ankle arteries may limit the predictive value of the ABI in individuals with diabetes; a limitation that may be overcome by measurement of the TBI.