Unmasking the enigma of lipid metabolism in metabolic dysfunction-associated steatotic liver disease: from mechanism to the clinic

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly defined as non-alcoholic fatty liver disease (NAFLD), is a disorder marked by the excessive deposition of lipids in the liver, giving rise to a spectrum of liver pathologies encompassing steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma. Despite the alarming increase in its prevalence, the US Food and Drug Administration has yet to approve effective pharmacological therapeutics for clinical use. MASLD is characterized by the accretion of lipids within the hepatic system, arising from a disarray in lipid provision (whether through the absorption of circulating lipids or de novo lipogenesis) and lipid elimination (via free fatty acid oxidation or the secretion of triglyceride-rich lipoproteins). This disarray leads to the accumulation of lipotoxic substances, cellular pressure, damage, and fibrosis. Indeed, the regulation of the lipid metabolism pathway is intricate and multifaceted, involving a myriad of factors, such as membrane transport proteins, metabolic enzymes, and transcription factors. Here, we will review the existing literature on the key process of lipid metabolism in MASLD to understand the latest progress in this molecular mechanism. Notably, de novo lipogenesis and the roles of its two main transcription factors and other key metabolic enzymes are highlighted. Furthermore, we will delve into the realm of drug research, examining the recent progress made in understanding lipid metabolism in MASLD. Additionally, we will outline prospective avenues for future drug research on MASLD based on our unique perspectives.

Silencing of Hepatic AATF Ameliorates Metabolic Dysfunction Associated Steatohepatitis by Promoting Fatty Acid β-Oxidation in Experimental models

“…Dysregulation of lipid metabolism is a hallmark of MASLD. Increased influx of free fatty acids (FFAs) from adipose tissue and dietary sources, along with impaired fatty acid oxidation and export of triglycerides from the liver, contribute to hepatic steatosis (10). Insulin resistance in hepatocytes leads to impaired suppression of gluconeogenesis and increased lipogenesis, promoting hepatic lipid accumulation (33).…”

“…MASLD manifests with the accumulation of lipids in the liver, stemming from disturbances in both lipid uptake (from circulating sources or de novo synthesis) and lipid disposal (via fatty acid oxidation or secretion of triglyceride-rich lipoproteins) (10). This disruption results in the buildup of lipotoxic compounds, cellular stress, injury, and fibrosis (10,11). The regulation of lipid metabolism is complex and multifaceted, involving various factors like membrane transporters, metabolic enzymes, and transcriptional regulators (12).…”

Pharmacological therapy of metabolic dysfunction-associated steatotic liver disease-driven hepatocellular carcinoma

“…Hepatocytes function as a major site for fat accumulation, making them a main target of lipotoxicity (Rao et al, 2023;Yahoo et al, 2023). IR in adipose tissue results in enhanced release of free FAs and delivery to the liver, allowing for excessive lipid accumulation and toxic metabolite-induced lipotoxicity, causing mitochondrial dysfunction and endoplasmic reticulum stress (ERS) (Venkatesan et al, 2023;Yahoo et al, 2023).…”

The clinician's view on the advantages and contradictions of the new nomenclature of steatotic liver disease: A review

“…Со временем эксперты начали обосновывать необходимость использования набора критериев для подтверждения данного диагноза. Предложенный подход основывался на том факте, что NAFLD является главным образом следствием системной метаболической дисфункции, в частности наличия МС [1,3,[18][19][20][21]. Другим обстоятельством, которое необходимо учитывать при обсуждении данной нозологии, представляется многофакторность этиопатогенеза, который включает особенности питания и потребления алкоголя, нарушение целостности кишечного барьера и особенности микробиоты кишечника, дисфункцию субклеточных структур (митохондрий, эндоплазматического ретикулума), а также нарушение обмена веществ и/или гормональные расстройства [20,[22][23][24][25][26][27].…”