Interplay between Liver, Kidney, and Heart in Metabolic Regulation and Cardioprotection: Mechanisms and Implications for Therapeutic Strategies

   Tom Akello Abbo

Department of Pharmacology, Kampala International University Uganda

ABSTRACT

The intricate interplay between the liver, kidney, and heart in metabolic regulation and cardioprotection is a topic of growing interest, particularly in the context of rising cardiovascular disease prevalence. This paper explores the dynamic interactions among these organs, highlighting their roles in energy metabolism, inflammation, and cardiovascular health. We discuss the mechanisms through which liver and kidney function impact cardioprotective properties, including the regulation of glucose and lipid metabolism, inflammation modulation, and remote conditioning effects. Furthermore, we examine the implications of liver-kidney-heart cross-talk for therapeutic strategies targeting cardiometabolic disorders. Understanding these complex interactions is essential for the development of innovative treatments to mitigate the burden of cardiovascular disease.

Keywords: Liver, Kidney, Heart, Cardioprotection and Therapy

INTRODUCTION

The heart interacts with other metabolic organs, like the liver and kidney, to optimize energy metabolism in order to meet the demands of increasing cardiac workload; evolving fuel requirements between fed and fasted periods conserved between mice and man [1-5]. In response to increasing cardiac workloads or β-adrenergic stimulation, the heart has the capacity to increase its oxidation of not only glucose (i.e., the main source of energy in the normal fed condition) but also fatty acids (in the normal fasted condition), both of which are stored in highly abundant quantities in adipocytes, as long-chain triglycerides [6-8]. In response to an activation of the γ-adrenergic system, adipose tissue can also hydrolyze intracellular triglycerides, releasing free fatty acids (FFAs) (plentiful in the fasted state) and glycerol [9-11]. Induction of cytosolic malate production in the stunned heart, from enhanced glycolytic-derived pyruvate, could supply a shunt for substrate malonyl CoA synthesis at the carboxylase enzymatic step, enabled from malate-pyruvate recycling; the cytosolic reduction of oxaloacetate to malate in the presence of an excess NADH for the shuttling of reducing potential from the cytosol to the mitochondria [12-15]. Diverging from the classical dogma of fuel partitioning where increased glucose oxidation is thought to be cardioprotective, it was observed that chronic stimulation of cardiac glucose utilization (by deletion of heart-specific histone deacetylase 2) could augment injury, in part by reducing oxidation of the essential endogenous protective substrate oleate [16-18]. The prevalence of cardiovascular disease continues to rise in Western societies, making the incidence and management of these pathologies an important public health issue. Indeed, myocardial infarction is still the leading cause of death in the free world [19-22]. Increases in the patient prevalence of obesity, metabolic syndrome, and type-2 diabetes (T2D) have exacerbated the rise in cardiovascular disease, and almost 30% of the general population is now considered obese, increasing the likelihood of further diabetic and non-diabetic cardiovascular disease events [23-25]. Therefore, understanding metabolic pathways and their organ-specific responses to cardioprotective interventions is critical toward creating innovative therapeutic strategies, especially given the recent failure of industry-sponsored clinical trials examining DPP-4 inhibitors and GLP-1 in the T2D population.