Kidney tubules use fatty acid oxidation (FAO) to support their high energetic requirements. Carnitine palmitoyltransferase 1A (CPT1A) is the rate-limiting enzyme for FAO, and it is necessary to transport long-chain fatty acids into mitochondria. To define the role of tubular CPT1A in aging and injury, we generated mice with tubule-specific deletion of Cpt1a ( Cpt1a ^CKO mice), and the mice were either aged for 2 years or injured by aristolochic acid or unilateral ureteral obstruction. Surprisingly, Cpt1a ^CKO mice had no significant differences in kidney function or fibrosis compared with wild-type mice after aging or chronic injury. Primary tubule cells from aged Cpt1a ^CKO mice had a modest decrease in palmitate oxidation but retained the ability to metabolize long-chain fatty acids. Very-long-chain fatty acids, exclusively oxidized by peroxisomes, were reduced in kidneys lacking tubular CPT1A, consistent with increased peroxisomal activity. Single-nuclear RNA-Seq showed significantly increased expression of peroxisomal FAO enzymes in proximal tubules of mice lacking tubular CPT1A. These data suggest that peroxisomal FAO may compensate in the absence of CPT1A, and future genetic studies are needed to confirm the role of peroxisomal β-oxidation when mitochondrial FAO is impaired.

The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.

ACE2 has emerged as a double agent in the COVID-19 ordeal being physiologically protective yet conducive of viral infection. The identification of ACE2 in as many as 72 tissues suggests that extra-pulmonary invasion and damage is likely, which indeed has already been demonstrated by cardiovascular and gastro-intestinal symptoms. On the other hand, identifying ACE2 dysregulation in patients with co-morbidities may offer insight as to why COVID-19 symptoms are often more severe in these individuals. This may be attributed to a pre-existing pro-inflammatory state that is further propelled with the cytokine storm induced by SARS-CoV-2 infection or the loss of functional ACE2 expression as a result of viral internalization. Here, we aim to characterize the distribution and role of ACE2 in various organs in order to highlight the scope of damage that may arise upon SARS-CoV-2 invasion. Furthermore, by examining the disruption of ACE2 in several co-morbid diseases, we offer insight into potential causes of increased severity of COVID-19 symptoms in certain individuals. Significance Statement Cell surface expression of ACE2 determines the tissue susceptibility for COVID-19 infection. Co-morbid disease conditions altering ACE2 expression could increase the patient’s vulnerability for the disease and its complications directly through modulation of viral infection, or indirectly through alteration of inflammatory status.

Aged, Cpt1a CKO panel. The correct panel is shown below.