Taxonomy: 2020

Ketone bodies can become a major source of adenosine triphosphate (ATP) production during stress to maintain bioenergetic homeostasis in the brain, heart and skeletal muscles. In the normal heart, ketone bodies contribute from 10 to 15% of the cardiac ATP production, while their contribution during pathological stress is still not well characterized and currently represents an exciting area of cardiovascular research. This review focuses on the mechanisms which regulate circulating ketone levels under physiological and pathological conditions and how this impacts cardiac ketone metabolism. We also review the current understanding of the role of augmented ketone metabolism as an adaptive response in different types and stages of heart failure. This includes the emerging experimental and clinical evidence of the potential favourable effects of boosting ketone metabolism in the failing heart and the possible mechanisms of action through which these interventions may mediate their cardioprotective effects. We also critically appraise the emerging data from animal and human studies which characterize the role of ketones in mediating the cardioprotection established by the new class of anti-diabetic drugs, namely sodium-glucose co-transporter inhibitors (SGLT2i). Read here

Glucolipotoxicity following nutrient overload causes cardiomyocyte injury by inhibiting TFEB and suppressing lysosomal function. We ascertained whether in addition to the amount, the type of fatty acids (FAs) and duration of FA exposure regulate TFEB action and dictate cardiomyocyte viability. Saturated FA, palmitate, but not polyunsaturated FAs decreased TFEB content in a concentration- and time-dependent manner in cardiomyocytes. Hearts from high-fat high-sucrose diet-fed mice exhibited a temporal decline in nuclear TFEB content with marked elevation of diacylglycerol and triacylglycerol, suggesting that lipid deposition and TFEB loss are concomitant molecular events. Next, we examined the identity of signaling and metabolic pathways engaged by the loss of TFEB action in the cardiomyocyte. Transcriptome analysis in murine cardiomyocytes with targeted deletion of myocyte TFEB (TFEB^-/-) revealed enrichment of differentially expressed genes (DEG) representing pathways of nutrient metabolism, DNA damage and repair, cell death and cardiac function. Strikingly, genes involved in macroautophagy, mitophagy and lysosome function constituted a small portion of DEGs in TFEB^-/- cardiomyocytes. In myoblasts and/or myocytes, nutrient overload-induced lipid droplet accumulation and caspase-3 activation were exacerbated by silencing TFEB or attenuated by overexpressing constitutively active TFEB. The effect of TFEB overexpression were persistent in the presence of Atg7 loss-of-function, signifying that the effect of TFEB in the myocyte is independent of changes in the macroautophagy pathway. In the cardiomyocyte, the non-canonical effect of TFEB to reprogram energy metabolism is more evident than the canonical action of TFEB on lysosomal autophagy. Loss of TFEB function perturbs metabolic pathways in the cardiomyocyte and renders the heart prematurely susceptible to nutrient overload-induced injury. Read here

Lysosomes are the main proteolytic compartments of mammalian cells comprising of a battery of hydrolases. Lysosomes dispose and recycle extracellular or intracellular macromolecules by fusing with endosomes or autophagosomes through specific waste clearance processes such as chaperone-mediated autophagy or microautophagy. The proteolytic end product is transported out of lysosomes via transporters or vesicular membrane trafficking. Recent studies have demonstrated lysosomes as a signaling node which sense, adapt and respond to changes in substrate metabolism to maintain cellular function. Lysosomal dysfunction not only influence pathways mediating membrane trafficking that culminate in the lysosome but also govern metabolic and signaling processes regulating protein sorting and targeting. In this review, we describe the current knowledge of lysosome in influencing sorting and nutrient signaling. We further present a mechanistic overview of intra-lysosomal processes, along with extra-lysosomal processes, governing lysosomal fusion and fission, exocytosis, positioning and membrane contact site formation. This review compiles existing knowledge in the field of lysosomal biology by describing various lysosomal events necessary to maintain cellular homeostasis facilitating development of therapies maintaining lysosomal function. Read here

Deregulation of lipid metabolism and insulin function in muscle and adipose tissue are hallmarks of systemic insulin resistance, which can progress to type 2 diabetes. While previous studies suggested that milk proteins influence systemic glucose homeostasis and insulin function, it remains unclear whether bioactive peptides generated from whey alter lipid metabolism and its accumulation in muscle and adipose tissue. Therefore, we incubated murine 3T3-L1 preadipocytes and C2C12 myotubes with a whey peptide mixture produced through pepsin-pancreatin digestion, mimicking peptides generated in the gut from whey protein hydrolysis, and examined its effect on indicators of lipid metabolism and insulin sensitivity. Whey peptides, particularly those derived from bovine serum albumin (BSA), promoted 3T3-L1 adipocyte differentiation and triacylglycerol (TG) accumulation in accordance with peroxisome proliferator-activated receptor γ (PPARγ) upregulation. Whey/BSA peptides also increased lipolysis and mitochondrial fat oxidation in adipocytes, which was associated with the upregulation of peroxisome proliferator-activated receptor δ (PPARδ). In C2C12 myotubes, whey but not BSA peptides ameliorated palmitate-induced insulin resistance, which was associated with reduced inflammation and diacylglycerol accumulation, and increased sequestration of fatty acids in the TG pool. Taken together, our study suggests that whey peptides generated via pepsin-pancreatin digestion profoundly alter lipid metabolism and accumulation in adipocytes and skeletal myotubes. Read here