Hepatic Insulin Clearance: A Novel Therapeutic Target in Type 2 Diabetes

This research program focuses on the genetic and mechanistic determinants of common metabolic diseases, including obesity, diabetes and dyslipidemia. Given the use of both naturally occurring mouse genetic variation and human genetic data, the laboratory’s work links genetic discovery to mechanistic and translational studies that can inform new therapeutic strategies. A central theme in the lab is the identification of genes and pathways that govern lipid metabolism and insulin handling by the liver, with an eye toward novel interventions for metabolic disease.

The laboratory’s strategy uses two complementary discovery approaches. First, naturally occurring genetic variation in mice is exploited to discover loci and genes that give rise to metabolic phenotypes. Second, candidate genes highlighted by human genome-wide association studies (GWAS) are functionally characterized in engineered mouse models through overexpression and knock-down approaches, facilitating causal inference and mechanistic insight. These approaches are applied across molecular, cellular and organismal levels, enabling the lab to trace how genetic variation influences protein function, cellular processes and whole-animal physiology.

A prominent focus of the Peterfy Lab is the Lipase Maturation Factor 1 (LMF1) gene, originally discovered in a mouse strain with combined lipase deficiency and severe hyperlipidemia. LMF1 functions as an endoplasmic reticulum chaperone required for the post-translational activation of several lipases integral to plasma lipid metabolism, including lipoprotein lipase (LPL), hepatic lipase (HL) and endothelial lipase (EL). Loss of functional LMF1 leads to inactive lipases and impaired triglyceride clearance, producing elevated circulating lipids; analogous human LMF1 mutations associate with lipase deficiency and hypertriglyceridemia. Current lab efforts aim to delineate tissue-specific roles of LMF1 using conditional knock-out mouse models, define molecular mechanisms regulating LMF1 function through biochemical and molecular approaches, and explore lipase-independent roles of LMF1 in endoplasmic reticulum homeostasis using cell biological methods. Through structural and functional analyses, and by mapping mutations in mouse and human that affect LMF1, the lab seeks to illuminate how this chaperone influences lipid metabolism and metabolic disease risk.

Complementing the LMF1 work, the Peterfy Lab leverages human GWAS signals for plasma lipid traits to nominate and validate novel genes that influence cholesterol and triglyceride levels. Major aims include functional validation of candidate genes in vivo, elucidation of the molecular mechanisms by which these genes alter plasma lipid levels, and identification of causative genomic variants through functional analyses of lipid-associated haplotypes. This translational pipeline—from human genetic association to mouse model validation and mechanistic dissection—positions the lab to identify potential therapeutic targets.

Publications from the group connect these lipid-focused investigations to insulin sensitivity and clearance, including studies on aging, hepatic insulin resistance, and relationships among hepatic lipase activity, lipid traits and insulin clearance. The Peterfy Laboratory’s genetics-driven, mechanistic research program advances understanding of hepatic lipid and insulin handling, aiming to reveal novel therapeutic targets for disorders such as type 2 diabetes and hypertriglyceridemia.