Liprin-α1 contributes to oncogenic MAPK signaling by counteracting ERK activity.

PTPRF interacting protein alpha 1 (PPFIA1) encodes for liprin-α1, a member of the leukocyte common antigen-related protein tyrosine phosphatase (LAR-RPTPs)-interacting protein family. Liprin-α1 localizes to adhesive and invasive structures in the periphery of cancer cells, where it modulates migration and invasion in head and neck squamous cell carcinoma (HNSCC) and breast cancer. To study the possible role of liprin-α1 in anticancer drug responses, we screened a library of oncology compounds in cell lines with high endogenous PPFIA1 expression. The compounds with the highest differential responses between high PPFIA1-expressing and silenced cells across cell lines were inhibitors targeting mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinases (ERK) signaling. KRAS proto-oncogene, GTPase (KRAS)-mutated MDA-MB-231 cells were more resistant to trametinib upon PPFIA1 knockdown compared with control cells. In contrast, liprin-α1-depleted HNSCC cells with low RAS activity showed a context-dependent response to MEK/ERK inhibitors. Importantly, we showed that liprin-α1 depletion leads to increased p-ERK1/2 levels in all our studied cell lines independent of KRAS mutational status, suggesting a role of liprin-α1 in the regulation of MAPK oncogenic signaling. Furthermore, liprin-α1 depletion led to more pronounced redistribution of RAS proteins to the cell membrane. Our data suggest that liprin-α1 is an important contributor to oncogenic RAS/MAPK signaling, and the status of liprin-α1 may assist in predicting drug responses in cancer cells in a context-dependent manner.

How to Measure Foot Self-Care? A Methodological Review of Instruments.

Foot self-care is an important element of caring for and promoting foot health. However, little is known about the validity and reliability of existing foot self-care instruments. The purpose of this review is to describe and analyze the focus, content, and psychometric evidence of existing instruments for measuring foot self-care. A methodological review of three international scientific databases-Medline (PubMed), CINAHL (Ebsco), and Embase-was conducted in May 2022. The search produced 3520 hits, of which 53 studies were included in the final analysis based on a two-phase selection process. A total of 31 instruments were identified, of which six were observed to have been used more than once. Subsequently, the methodological quality of these six instruments was evaluated. It is noted that although a considerable variety of instruments are used in measuring foot self-care, only a small proportion are used consistently. In general, the psychometric testing instruments seem to primarily focus on analyzing content validity and homogeneity. In the future, comprehensive testing of instrument psychometrics could enhance the cumulative evidence of the methodological quality of these instruments. Furthermore, researchers and clinicians can use the information in this review to make informed choices when selecting an instrument for their purposes.

Mitochondrial 2,4-dienoyl-CoA reductase (Decr) deficiency and impairment of thermogenesis in mouse brown adipose tissue.

A large number of studies have demonstrated significance of polyunsaturated fatty acids (PUFAs) for human health. However, many aspects on signals translating PUFA-sensing into body homeostasis have remained enigmatic. To shed light on PUFA physiology, we have generated a mouse line defective in mitochondrial dienoyl-CoA reductase (Decr), which is a key enzyme required for ß-oxidation of PUFAs. Previously, we have shown that these mice, whose oxidation of saturated fatty acid is intact but break-down of unsaturated fatty acids is blunted, develop severe hypoglycemia during metabolic stresses and fatal hypothermia upon acute cold challenge. In the current work, indirect calorimetry and thermography suggested that cold intolerance of Decr-/- mice is due to failure in maintaining appropriate heat production at least partly due to failure of brown adipose tissue (BAT) thermogenesis. Magnetic resonance imaging, electron microscopy, mass spectrometry and biochemical analysis showed attenuation in activation of lipolysis despite of functional NE-signaling and inappropriate expression of genes contributing to thermogenesis in iBAT when the Decr-/- mice were exposed to cold. We hypothesize that the failure in turning on BAT thermogenesis occurs due to accumulation of unsaturated long-chain fatty acids or their metabolites in Decr-/- mice BAT suppressing down-stream propagation of NE-signaling.

Mitochondrial fatty acid synthesis, fatty acids and mitochondrial physiology.

Mitochondria and fatty acids are tightly connected to a multiplicity of cellular processes that go far beyond mitochondrial fatty acid metabolism. In line with this view, there is hardly any common metabolic disorder that is not associated with disturbed mitochondrial lipid handling. Among other aspects of mitochondrial lipid metabolism, apparently all eukaryotes are capable of carrying out de novo fatty acid synthesis (FAS) in this cellular compartment in an acyl carrier protein (ACP)-dependent manner. The dual localization of FAS in eukaryotic cells raises the questions why eukaryotes have maintained the FAS in mitochondria in addition to the "classic" cytoplasmic FAS and what the products are that cannot be substituted by delivery of fatty acids of extramitochondrial origin. The current evidence indicates that mitochondrial FAS is essential for cellular respiration and mitochondrial biogenesis. Although both ß-oxidation and FAS utilize thioester chemistry, CoA acts as acyl-group carrier in the breakdown pathway whereas ACP assumes this role in the synthetic direction. This arrangement metabolically separates these two pathways running towards opposite directions and prevents futile cycling. A role of this pathway in mitochondrial metabolic sensing has recently been proposed. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.

USF1 deficiency activates brown adipose tissue and improves cardiometabolic health.

USF1 (upstream stimulatory factor 1) is a transcription factor associated with familial combined hyperlipidemia and coronary artery disease in humans. However, whether USF1 is beneficial or detrimental to cardiometabolic health has not been addressed. By inactivating USF1 in mice, we demonstrate protection against diet-induced dyslipidemia, obesity, insulin resistance, hepatic steatosis, and atherosclerosis. The favorable plasma lipid profile, including increased high-density lipoprotein cholesterol and decreased triglycerides, was coupled with increased energy expenditure due to activation of brown adipose tissue (BAT). Usf1 inactivation directs triglycerides from the circulation to BAT for combustion via a lipoprotein lipase-dependent mechanism, thus enhancing plasma triglyceride clearance. Mice lacking Usf1 displayed increased BAT-facilitated, diet-induced thermogenesis with up-regulation of mitochondrial respiratory chain complexes, as well as increased BAT activity even at thermoneutrality and after BAT sympathectomy. A direct effect of USF1 on BAT activation was demonstrated by an amplified adrenergic response in brown adipocytes after Usf1 silencing, and by augmented norepinephrine-induced thermogenesis in mice lacking Usf1. In humans, individuals carrying SNP (single-nucleotide polymorphism) alleles that reduced USF1 mRNA expression also displayed a beneficial cardiometabolic profile, featuring improved insulin sensitivity, a favorable lipid profile, and reduced atherosclerosis. Our findings identify a new molecular link between lipid metabolism and energy expenditure, and point to the potential of USF1 as a therapeutic target for cardiometabolic disease.