Dissection of surface area-dependent lipolysis at a single organelle level.

Lipid droplets are dynamic organelles whose size and number signify their role in energy. However, owing to cellular heterogeneity and technological limitations, the relationship between the lipolytic ability and lipid droplet morphology is unclear. Here, we developed a live-cell imaging assay using geometric analysis to quantify cellular lipolysis at a single organelle level, designated imaging lipolysis.

HSP90 deficiency promotes cholesteryl ester accumulation in lipid droplets via endocytosis of low-density lipoprotein.

The size and number of lipid droplets (LDs), as intracellular lipids storage organelles, are closely correlated to lipid metabolism. However, the regulation of lipid metabolism is still unclear. Here, based on changes in three LD phenotypic indicators, including LD number, average LD area, and total LD amount in a cell, we establish an imaging-based high-throughput screen on a compound library.

DHHC5 regulates lacteal function and intestinal lipid absorption by maintaining VEGFR2 localization in lipid rafts.

The intestinal lymphatic system is essential for lipid absorption, yet its regulatory mechanisms remain poorly understood. Here, we identify DHHC5, an Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferase, as a critical regulator of intestinal lymphatic integrity and lipid uptake. Whole-body inducible knockout () mice were resistant to diet-induced obesity and exhibited impaired intestinal lipid absorption due to lymphatic dysfunction.

A lysosomal surveillance response to stress extends healthspan.

Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%.

CIDEC/FSP27 exacerbates obesity-related abdominal aortic aneurysm by promoting perivascular adipose tissue inflammation.

Abdominal aortic aneurysm (AAA) is strongly correlated with obesity, partially due to the abnormal expansion of abdominal perivascular adipose tissue (PVAT). Cell death-inducing DNA fragmentation factor-like effector C (CIDEC), also known as fat-specific protein 27 (FSP27) in rodents, is specifically expressed in adipose tissue where it mediates lipid droplet fusion and adipose tissue expansion. Whether and how CIDEC/FSP27 plays a role in AAA pathology remains elusive.

Context-specific fatty acid uptake is a finely-tuned multi-level effort.

Fatty acids (FAs) are essential nutrients that play multiple roles in cellular activities. To meet cell-specific needs, cells exhibit differential uptake of FAs in diverse physiological or pathological contexts, coordinating to maintain metabolic homeostasis. Cells tightly regulate the localization and transcription of CD36 and other key proteins that transport FAs across the plasma membrane in response to different stimuli.

Paxillin family proteins Hic-5 and LPXN promote lipid storage by regulating the ubiquitination degradation of CIDEC.

Many metabolic diseases are caused by disorders of lipid homeostasis. CIDEC, a lipid droplet (LD)-associated protein, plays a critical role in controlling LD fusion and lipid storage. However, regulators of CIDEC remain largely unknown.

TRiC/CCT chaperonin is required for the folding and inhibitory effect of WDTC1 on adipogenesis.

Obesity has become a global pandemic. WDTC1 is a WD40-containing protein that functions as an anti-obesity factor. WDTC1 inhibits adipogenesis by working as an adaptor of the CUL4-DDB1 E3 ligase complex.

ARF6 plays a general role in targeting palmitoylated proteins from the Golgi to the plasma membrane.

Protein palmitoylation is a post-translational lipid modification of proteins. Accumulating evidence reveals that palmitoylation functions as a sorting signal to direct proteins to destinations; however, the sorting mechanism remains largely unknown. Here, we show that ARF6 plays a general role in targeting palmitoylated proteins from the Golgi to the plasma membrane (PM).

Adipose triglyceride lipase: the first transacylase for FAHFAs.

In a recent article published in , Patel . identified adipose triglyceride lipase (ATGL, also known as patatin-like phospholipase domain containing 2) as the first biosynthetic enzyme of fatty acid esters of hydroxy fatty acids (FAHFAs), further expanding the knowledge on bioactive lipid research and being a potential paradigm shift for ATGL studies.

TMEM25 inhibits monomeric EGFR-mediated STAT3 activation in basal state to suppress triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor outcome and lacks of approved targeted therapy. Overexpression of epidermal growth factor receptor (EGFR) is found in more than 50% TNBC and is suggested as a driving force in progression of TNBC; however, targeting EGFR using antibodies to prevent its dimerization and activation shows no significant benefits for TNBC patients. Here we report that EGFR monomer may activate signal transducer activator of transcription-3 (STAT3) in the absence of transmembrane protein TMEM25, whose expression is frequently decreased in human TNBC.

PITPNC1 promotes the thermogenesis of brown adipose tissue under acute cold exposure.

Brown adipose tissue (BAT) plays an essential role in non-shivering thermogenesis. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) is identified as a lipid transporter that reciprocally transfers phospholipids between intracellular membrane structures. However, the physiological significance of PITPNC1 and its regulatory mechanism remain unclear.

DDB1 prepares brown adipocytes for cold-induced thermogenesis.

Brown adipose tissue (BAT) plays a key role in thermogenesis during acute cold exposure. However, it remains unclear how BAT is prepared to rapidly turn on thermogenic genes. Here, we show that damage-specific DNA binding protein 1 (DDB1) mediates the rapid transcription of thermogenic genes upon acute cold exposure.

DHHC5 facilitates oligodendrocyte development by palmitoylating and activating STAT3.

Myelin sheath is an important structure to maintain functions of the nerves in central nervous system. Protein palmitoylation has been established as a sorting determinant for the transport of myelin-forming proteins to the myelin membrane, however, its function in the regulation of oligodendrocyte development remains unknown. Here, we show that an Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases, DHHC5, is involved in the control of oligodendrocyte development.

The Mediator subunit MED20 organizes the early adipogenic complex to promote development of adipose tissues and diet-induced obesity.

MED20 is a non-essential subunit of the transcriptional coactivator Mediator complex, but its physiological function remains largely unknown. Here, we identify MED20 as a substrate of the anti-obesity CRL4-WDTC1 E3 ubiquitin ligase complex through affinity purification and candidate screening. Overexpression of WDTC1 leads to degradation of MED20, whereas depletion of WDTC1 or CUL4A/B causes accumulation of MED20.

DDB1 binds histone reader BRWD3 to activate the transcriptional cascade in adipogenesis and promote onset of obesity.

Obesity has become a global pandemic. Identification of key factors in adipogenesis helps to tackle obesity and related metabolic diseases. Here, we show that DDB1 binds the histone reader BRWD3 to promote adipogenesis and diet-induced obesity.

G-protein-coupled receptor GPR17 inhibits glioma development by increasing polycomb repressive complex 1-mediated ROS production.

Glioma is the most common primary tumor in the central nervous system. However, the development of glioma and effective therapeutic strategies remain elusive. Here, we identify GPR17 as a potential target to treat glioma.

Tissue-Specific Splicing and Dietary Interaction of a Mutant Allele Determine Muscle Metabolic Fitness in Rodents.

Ethnic groups are physiologically and genetically adapted to their diets. Inuit bear a frequent AS160 mutation that causes type 2 diabetes. Whether this mutation evolutionarily confers adaptation in Inuit and how it causes metabolic disorders upon dietary changes are unknown due to limitations in human studies.

AIDA directly connects sympathetic innervation to adaptive thermogenesis by UCP1.

The sympathetic nervous system-catecholamine-uncoupling protein 1 (UCP1) axis plays an essential role in non-shivering adaptive thermogenesis. However, whether there exists a direct effector that physically connects catecholamine signalling to UCP1 in response to acute cold is unknown. Here we report that outer mitochondrial membrane-located AIDA is phosphorylated at S161 by the catecholamine-activated protein kinase A (PKA).

Blocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression.

Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigeneses. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of and to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation.

CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis.

Fatty acids (FAs) are essential nutrients, but how they are transported into cells remains unclear. Here, we show that FAs trigger caveolae-dependent CD36 internalization, which in turn delivers FAs into adipocytes. During the process, binding of FAs to CD36 activates its downstream kinase LYN, which phosphorylates DHHC5, the palmitoyl acyltransferase of CD36, at Tyr91 and inactivates it.