Mechanisms of nonalcoholic steatohepatitis-associated cardiomyopathy: key roles for liver–heart crosstalk

Abstract

Purpose of reviewNonalcoholic steatohepatitis (NASH) is a multisystem disease that affects not only the liver but also heart, pancreas, and kidney. We currently lack a comprehensive understanding of mechanisms responsible for the development of NASH-associated cardiomyopathy or the influence of sex on pathophysiology. There is a critical need to address these gaps in knowledge in order to accelerate translation of knowledge into clinical practice. Recent findingsNASH and cardiovascular disease share common risk factors such as chronic inflammation, hyperlipidemia, and insulin resistance. Early cardiac dysfunction in NASH that is independent of obesity or other cardiometabolic risk factors suggests roles for liver--heart crosstalk in disease pathogenesis. Inflammation is a driving force in the pathogenesis of NASH, and it is likely that 'spill over' of NASH inflammation contributes to the development of cardiomyopathy. However, molecular and cellular mechanisms that mediate NASH-associated cardiomyopathy remain unclear because of inherent limitations of experimental models. Even so, recent studies implicate inflammatory, metabolic, and physiologic mechanisms that enhance our understanding of NASH-associated cardiomyopathy and the role of liver-heart crosstalk. SummaryAn innovative, detailed, and mechanistic understanding of NASH-associated cardiomyopathy is relevant to public health and will be fundamental for the comprehensive care of these patients.

Lipidomic signatures discriminate subtle hepatic changes in the progression of porcine nonalcoholic steatohepatitis

“…It has been shown that conventional dendritic cells produce The increase in plasma Cer(42:1), a long-fatty acid containing ceramide (d18:1/24:0), may contribute to potentiate lipotoxicity in muscle (51) but it did not experience changes in the liver. Although, in the present design, this was not translated into development of metabolic syndrome, some authors have raised this possibility (52,53). The increase in the absolute level of an individual NEFA (FA 16:0) without changes in total NEFA levels in pig point out that individual species of FA are more sensitive parameters of metabolic changes that total NEFA levels.…”

Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases

“…This dysregulation perhaps extends beyond hepatic boundaries, affecting systemic metabolic processes such as glucose uptake, glycogen synthesis, glucose and fat oxidation, lipid storage, and lipolysis. Ectopic fat deposition with increased inflammation resulting from MASLD and obesity in non-AT, pose a substantial risk factor for CVDs, highlighting the severe pathogenic impact of MASH beyond the liver ( Ferrara et al, 2019 ; Njoku et al, 2022 ). Defects in hepatic lipid metabolism not only precipitate intrahepatic lipid accumulation but also promotes lipid storage in non-hepatic tissues, highlighting the liver’s central role in systemic lipid homeostasis.…”

“…However, it is likely that systemic inflammation and spill over mechanisms play a role in promoting inflammation in other tissues. Central to the systemic nature of MASH is the concept of hepatic inflammatory “spill over,” where pro-inflammatory mediators produced in the liver ( Njoku et al, 2022 ), as a consequence of lipid accumulation and cell injury (lipotoxicity), disseminate through the bloodstream to distant organs ( Buzzetti et al, 2016 ; Loomba et al, 2021 ; Zhong et al, 2024 ). This process is facilitated by an array of cytokines, chemokines, and other inflammatory molecules, such as TNF-α, interleukins (e.g., IL-6, IL-1β), and C-reactive protein (CRP), which are elevated in the context of MASH ( Buzzetti et al, 2016 ; Machado and Diehl, 2016 ; Mitten and Baffy, 2022 ).…”

“…The precise mechanisms by which MASH contributes to cardiovascular pathology are not fully understood. However, emerging evidence suggests that hepatic fat accumulation serves as a predictor for impaired myocardial metabolism and subsequent cardiac dysfunction ( Ferrara et al, 2019 ; Lim et al, 2019 ; Njoku et al, 2022 ; Younossi et al, 2024a ; Wang et al, 2024 ). Furthermore, MASLD is strongly associated with structural and functional cardiac abnormalities, such as left ventricular hypertrophy, enhanced epicardial fat thickness, and various arrhythmogenic manifestations, likely stemming from the liver’s pivotal role in systemic glucose and lipid homeostasis ( Ismaiel and Dumitrascu, 2019 ; Patel and Siddiqui, 2019 ; Mantovani et al, 2022 ).…”

“…A key feature of MASLD and MASH, IR disrupts glucose homeostasis, promoting fat accumulation in the liver and progressing from simple steatosis to MASH and potentially to cirrhosis and liver failure ( Llovet et al, 2023 ; Cusi et al, 2024 ). IR fosters inflammation and oxidative stress, contributing to liver cell injury and disease progression ( Loomba et al, 2021 ; Muzurovic et al, 2022 ; Njoku et al, 2022 ). The complex mechanisms underlying IRinvolve genetic factors, obesity, inflammation, lipotoxicity, mitochondrial dysfunction, and hormonal imbalances ( Powell et al, 2021 ; Salah et al, 2021 ; Tripathi et al, 2022 ; Wong et al, 2023 ).…”