Biology subjects

Barrett-Wilt, G.

Publications and source records attributed to Barrett-Wilt, G..

2 recordsLinked to original sources

bioRxiv2026

TMEM135 deficiency remodels hepatic lipid homeostasis and protein malonylation through a DHA-sensitive lipogenic program buffered by peroxisomal metabolism

TMEM135 has been implicated in lipid metabolism, but its role in regulating hepatic lipid homeostasis remains unclear. Here, we investigated how TMEM135 affects hepatic lipid metabolism using Tmem135 mutant mice with liver-specific Pex5 deletion. The Tmem135 mutation induced a lipogenic state characterized by depletion of docosahexaenoic acid (DHA), activation of SREBP-dependent pathways, and increased monounsaturated fatty acids without causing hepatic steatosis. In contrast, loss of PEX5-dependent peroxisomal function in Tmem135 mutant mice resulted in marked hepatic lipid accumulation, indicating that peroxisomal metabolism buffers the elevated lipogenic state. Fish oil supplementation to Tmem135 mutant mice restored DHA levels and suppressed lipogenesis. Proteomics identified distinct DHA-sensitive metabolic programs, including activation of SREBP-dependent lipogenesis. Quantitative malonyl-proteomics revealed increased malonylation of glycolytic enzymes, accompanied by altered glycolytic output. Together, these findings identify TMEM135 as a central regulator of hepatic lipid metabolism and uncover a coordinated mechanism linking lipid availability, lipogenesis, and post-translational metabolic regulation. HighlightTmem135 mutation induces a lipogenic state with increased lipolysis without hepatic steatosis. PEX5-dependent peroxisomal function buffers lipid accumulation in Tmem135 mutant liver. Fish oil supplementation restores DHA and suppresses SREBP-dependent lipogenesis in Tmem135 mutants. DHA-sensitive protein malonylation targets glycolytic enzymes in Tmem135 mutant liver.

cell biology↗

bioRxiv2024

Dietary lipid is largely deposited in skin and rapidly affects insulating properties

Skin has been shown to be a regulatory hub for energy expenditure and metabolism: mutations of skin lipid metabolism enzymes can change the rate of thermogenesis and susceptibility to diet-induced obesity. However, little is known about the physiological basis for this function. Here we show that the thermal properties of skin are highly reactive to diet: within three days, a high fat diet reduces heat transfer through skin. In contrast, a dietary manipulation that prevents obesity accelerates energy loss through skins. We found that skin was the largest target in a mouse body for dietary fat delivery, and that dietary triglyceride was assimilated both by epidermis and by dermal white adipose tissue. Skin from mice calorie-restricted for 3 weeks did not take up circulating lipids and showed a highly depleted stratum corneum. Dietary triglyceride acyl groups persist in skin for weeks after feeding. Using multi-modal lipid profiling, we have implicated both keratinocytes and sebocytes in the altered lipids which correlate with thermal function. In response to high fat feeding, wax diesters and ceramides accumulate, and triglycerides become more saturated. In contrast, in response to the dramatic loss of adipose tissue that accompanies restriction of the branched chain amino acid isoleucine, skin becomes more heat-permeable, resisting changes induced by Western diet feeding, with a signature of depleted signaling lipids. We propose that skin should be routinely included in physiological studies of lipid metabolism, given the size of the skin lipid reservoir and its adaptable functionality.

physiology↗