Biology subjects

Yen, C.-L. E.

Publications and source records attributed to Yen, C.-L. E..

3 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↗

bioRxiv2020

Contrasting recruitment of skin-associated adipose depots during cold challenge of mouse and human

Mammalian skin impacts metabolic efficiency system-wide, controlling the rate of heat loss and consequent heat production. Here we compare the unique fat depots associated with mouse and human skin, to determine whether they have corresponding function and regulation. For human, we assay a skin-associated fat (SAF) body-wide depot to distinguish it from the subcutaneous fat pads characteristic of abdomen and upper limbs. We show that the thickness of SAF is not related to general adiposity; it is much thicker (1.6-fold) in women than men, and highly subject-specific. We used molecular and cellular assays of {beta}-adrenergic induced lipolysis and found that dermal white adipose tissue (dWAT) in mice is resistant to lipolysis; in contrast, the body-wide human SAF depot becomes lipolytic, generating heat in response to {beta}-adrenergic stimulation. In mice challenged to make more heat to maintain body temperature (either environmentally or genetically), there is a compensatory increase in thickness of dWAT: A corresponding {beta}-adrenergic stimulation of human skin adipose (in vivo or in explant) depletes adipocyte lipid content. We summarize the regulation of skin-associated adipocytes by age, sex, and adiposity, for both species. We conclude that the body-wide dWAT depot of mice shows unique regulation that enables it to be deployed for heat preservation; combined with the actively lipolytic subcutaneous mammary fat pads they enable thermal defense. The adipose tissue that covers human subjects produces heat directly, providing an alternative to the brown adipose tissues. KEY POINTS SUMMARYO_LISeveral distinct strategies produce and conserve heat to maintain body temperature of mammals, each associated with unique physiologies, with consequence for wellness and disease susceptibility C_LIO_LIHighly regulated properties of skin offset the total requirement for heat production C_LIO_LIWe hypothesize that the adipose component of skin is primarily responsible for modulating heat flux; here we evaluate the relative regulation of adipose depots in mouse and human, to test their recruitment to heat production and conservation C_LIO_LIWe found that insulating mouse dermal white adipose tissue accumulates in response to environmentally- and genetically-induced cool stress; this layer is one of two adipose depots closely apposed to mouse skin, where the subcutaneous mammary gland fat pads are actively recruited to heat production C_LIO_LIIn contrast, the body-wide adipose depot associated with human skin produces heat directly, potentially creating an alternative to the centrally regulated brown adipose tissue C_LI

physiology↗