Intrahepatic lipid content (IHL)

Intrahepatic lipid content (IHL) represents the accumulation of triglycerides within the cytoplasm of hepatocytes and is the hallmark of fatty liver diseases such as Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). IHL is not a discrete molecular target like an enzyme or receptor, but rather a phenotypic measurement and key clinical biomarker used to assess the severity of hepatic steatosis and the efficacy of metabolic drugs. Elevated IHL is tightly linked to systemic insulin resistance, dyslipidemia, and an increased risk of progression to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and cirrhosis (NIH/NIDDK, 2023). In drug development, IHL is often the primary or secondary endpoint in Phase 2 clinical trials, where it is measured non-invasively using Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF). Therapeutic strategies to reduce IHL involve targeting upstream molecular pathways, such as the activation of Thyroid Hormone Receptor Beta (THR-β) or the modulation of incretin receptors (GLP-1R/GIPR), which promote the breakdown of fats or inhibit the synthesis of new lipids (PubMed: 31070527). Consequently, while IHL serves as a target for reduction in clinical practice, the actual pharmacological targets are the proteins and signaling pathways that regulate hepatic lipid flux.

Other names

Intrahepatic triglyceridesHepatic fat fractionLiver fat contentIHTGHepatic steatosisIHLC

Drugs do not bind to intrahepatic lipid content directly; instead, they target metabolic pathways such as thyroid hormone receptor beta activation, GLP-1 receptor agonism, or PPAR modulation to decrease de novo lipogenesis and increase fatty acid oxidation, thereby reducing the lipid volume stored in hepatocytes.