Hepatic Lipoprotein Production, Cardiometabolic Phenotypes, and Subtypes of Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) impacts more than a third of adults worldwide. The burgeoning epidemic of MASLD has led to increases in atherosclerotic cardiovascular disease (CVD), which is the leading cause of morbidity and mortality among affected individuals, particularly those with type 2 diabetes. Subsets of patients with MASLD will develop progressive liver disease, including metabolic dysfunction-associated steatohepatitis, advanced fibrosis, cirrhosis, and hepatocellular cancer. The association of progressive forms of MASLD with cardiometabolic disease has spurred interest in understanding how distinct pathways in hepatic lipid and lipoprotein metabolism may identify candidate therapeutic targets to mitigate CVD risk. A deeper understanding of hepatic lipid and lipoprotein homeostasis in MASLD is a pressing need for several reasons connected with some of the molecular and signaling adaptations occurring in obesity and type 2 diabetes. First, because these conditions individually and in combination accelerate the onset and progression of MASLD; second, because progressive MASLD may promote insulin resistance and type 2 diabetes; and third, because some CVD risk factors (dyslipidemia, obesity, type 2 diabetes) overlap with those for MASLD. Evidence suggests a multifactorial cause for MASLD, including genetic factors that either promote or mitigate liver disease progression and which, along with environmental modifiers (diet, obesity) and insulin resistance, contribute to CVD risk. Segregating these causes of MASLD by phenotype/metabotype reveals a systemic metabolic dysfunction (obesity, insulin resistance) dominant subtype, which is associated with increased CVD, and a second dominant subtype where familial and genetic factors predominate, which reflects impaired VLDL (very low-density lipoprotein) secretion and is associated with reduced CVD risk. Further study of these distinctive subtypes of MASLD may identify new, tailored approaches to prevent cardiometabolic disease.