Lipid metabolism in MASLD and MASH: From mechanism to the clinic

Abstract

Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is recognised as a metabolic disease characterised by excess intrahepatic lipid accumulation due to lipid overflow and synthesis, alongside impaired oxidation and/or export of these lipids. But where do these lipids come from? The main pathways related to hepatic lipid accumulation are de novo lipogenesis and excess fatty acid transport to the liver (due to increased lipolysis, adipose tissue insulin resistance, as well as excess dietary fatty acid intake, in particular of saturated fatty acids). Not only triglycerides but also other lipids are secreted by the liver and are associated with a worse histological profile in MASH, as shown by lipidomics. Herein, we review the role of lipid metabolism in MASLD/MASH and discuss the impact of weight loss (diet, bariatric surgery, GLP-1RAs) or other pharmacological treatments (PPAR or THRβ agonists) on hepatic lipid metabolism, lipidomics, and the resolution of MASH.

Keywords: Non-esterified fatty acids; de novo lipogenesis; diet composition; hepatic lipid metabolism; mitochondrial function.

Graphical abstract

Fig. 1

Lipid droplet biogenesis. Non-esterified FFAs from lipolysis or de novo lipogenesis are re-esterified into TAGs by DGAT1 and DGAT2 in the ER. Palmitate is the first FFA synthesised in the DNL by the enzymatic complex FASN; synthesis begins by combining acetyl-CoA with malonyl-CoA. Palmitate is elongated to stearate by ELOV6 and desaturated by SCD1 to palmitolate and oleate. Lipid droplets contain TAGs and sterol esters and are surrounded by a phospholipid monolayer with proteins from PLIN family members. Lipid droplets expand through droplet-droplet fusion or TAG transfer to or synthesis on the lipid droplet surface. DGAT1/2, diacylglycerol acyltransferase 1/2; DNL, de novo lipogenesis; ELOV6, fatty acid elongase-6; ER, endoplasmic reticulum; FASN, fatty acid synthase; FFAs, free fatty acids; LDs, lipid droplets; PLIN, perilipin; SCD1, stearoyl-CoA desaturase-1; TAGs, triacylglycerols.

Fig. 2

Percentage of participants with resolution of MASH and no worsening of fibrosis (defined as no increase in the fibrosis stage) in clinical trials with different treatments. (A) Diet and physical activity for 1-year; (B) bariatric surgery for 1 year; (C) GLP-1 receptor agonist semaglutide for 72-weeks; (D) pioglitazone for 18 months; (E) lanifibranor for 24 weeks; (F) the THRβ agonist resmetirom for 52 weeks; (G) the dual GLP-1-GIP agonist tirzepatide for 52 weeks; (H) dual GLP-1/glucagon agonist survodutide for 48 weeks. GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide 1; MASH, metabolic dysfunction-associated steatohepatitis; THR, thyroid hormone receptor.

Fig. 3

Synthesis of ceramides. De novo synthesis of ceramide occurs in the ER where the condensation of palmitate and serine (by the enzyme SPT) forms 3-keto-dihydrosphingosine which is reduced to dihydrosphingosine and acetylated by the CerS to produce dihydroceramide. DES1 and DES2 insert an unsaturation into the sphingosine backbone to produce ceramides. Ceramides can also be synthesised via the salvage pathway from hydrolysis of sphingomyelins catalysed by SMase. Ceramides are transported from the ER to the Golgi by either vesicular trafficking or by the ceramide transfer protein and can be further metabolized to sphingomyelins, complex glycosphingolipids, phosphorylated into ceramide-1-phosphate or transformed into sphingosines and phosphorylated by sphingosine kinase to form sphingosine-1-phosphate. ER, endoplasmic reticulum.