NEW YORK (GenomeWeb) – Researchers in China have discovered a protein that regulates the uptake of dietary cholesterol in the gut, and which might serve as a drug target to keep blood cholesterol levels in check and prevent heart disease.
A truncated version of the protein, called LIMA1, has led to unusually low levels of low-density lipoprotein cholesterol (LDL-C) and reduced cholesterol absorption in a family of Chinese Kazahks, the researchers found, and additional experiments in mice further explored the molecular role of LIMA1.
The team, led by scientists at Wuhan University and Xinjian Medical University, published its findings in Science today.
High levels of LDL-C in the blood are a known risk factor for cardiovascular disease. Up to 50 percent of variance in LDL-C concentration are thought to be genetic, but known genetic factors only explain a fraction of the observed variation. To find new LDL-C-associated genetic variants, the researchers homed in on Chinese Kazakhs, an isolated ethnic group in western China that differs genetically from other populations and in whom lipid genetics studies had not been conducted yet.
Specifically, they focused on a Chinese Kazakh family with inherited low levels of LDL-C, sequencing the exomes of three family members with low LDL-C and one with normal LDL-C. This led them to seven candidate variants, of which only one — a truncating frameshift deletion in the LIMA1 gene (also known as EPLIN and SREBP3) — cosegregated with the low LDL-C phenotype in the family.
In general, LDL-C levels are influenced by both the body's own cholesterol synthesis and by the uptake of dietary cholesterol in the intestine. Mass spec-based analysis of cholesterol-related compounds in family members with the LIMA1 mutation showed that their intestinal cholesterol absorption was impaired, suggesting a role for LIMA1 in that process.
Targeted sequencing of LIMA1 in 509 additional Chinese Kazakh individuals with low LDL-C levels found that one carried the same mutation as the family, whereas none of 510 Chinese Kazakhs with normal LDL-C levels did. The researchers also discovered three additional families, all with low LDL-C levels, who had a different LIMA1 mutation that appears to destabilize the protein.
To further investigate the function of LIMA1 in cholesterol metabolism, they conducted a number of studies in mice. The protein appears to be most highly expressed in the small intestine, especially in the brush border membrane, and mice lacking LIMA1 in their intestines showed lower cholesterol uptake than wild-type mice.
Further studies revealed that LIMA1 probably acts as a scaffold protein that forms a triplex complex with NPC1L1, a transmembrane protein that facilitates the uptake of cholesterol through vesicles, and myosin Vb.
Ultimately, the scientists concluded, LIMA1 might serve as a new drug target to lower LDL-C in patients. "A growing body of evidence has indicated that lower LDL-C levels are associated with reduced risk of [cardiovascular disease]," they wrote, adding that although LDL-C can already be decreased by statins and other drugs, "inhibition of LIMA may provide a new direction for treating hypercholesterolemia."