• How Could Variants in TM6SF2 Affect Risk for NAFLD?

How Could Variants in TM6SF2 Affect Risk for NAFLD?

The human transmembrane 6 superfamily member 2 (TM6SF2) protein regulates cholesterol metabolism in mice, researchers report in the May issue of Gastroenterology. These findings provide insight into the how a variant of TM6SF2 (encoding the amino acid change E167K) reduces total cholesterol and low-density lipoprotein cholesterol (LDL-c) levels in humans, and its potential as a therapeutic target.

A coding variant (E167K) in the human transmembrane 6 superfamily member 2 (TM6SF2) gene has been associated with hepatic and plasma levels of triglyceride and cholesterols, reducing risk for cardiovascular disease but increasing the risk for nonalcoholic fatty liver disease (NAFLD). People who carry the E167K have lower blood levels of total cholesterol, LDL-c, and triglycerides.

TM6SF2 is highly expressed in the liver and small intestine of humans and mice, and localizes to the endoplasmic reticulum—an active site of cholesterol metabolism. TM6SF2 is a member of the EBP superfamily (EXPERA) domain-containing protein, and might convert zymosterol to 5-α-cholesta-7,24-dien-3β-ol —an important step in cholesterol biosynthesis.

Yanbo Fan et al. studied the effects of expressing the human form of TM6SF2 on cholesterol metabolism in mice.

Mice that expressed the human TM6SF2 transgene specifically in liver had increased plasma levels of total cholesterol and LDL-c, compared with control mice, and altered liver expression of genes that regulate cholesterol metabolism.  There were no obvious changes in histologic features of livers in these mice.

When the mice were placed on a high-fat diet for 10 weeks, levels of total cholesterol and LDL-c increased further—by 27.6% and 70.9%, respectively. There was no difference in body weight, but the ratio of liver weight to body weight increased by 47.8%.

Decreased plasma levels of total cholesterol, HDL-c, and LDL-c in TM6SF2-knockout mice fed a high-fat diet for 12 weeks.

Decreased plasma levels of total cholesterol (TC), HDL-c, and LDL-c in TM6SF2-knockout mice fed a high-fat diet for 12 weeks.

On the other hand, TM6SF2-knockout mice had decreased plasma levels of total cholesterol compared with control mice. After 12 weeks on a high-fat diet, levels of total cholesterol, LDL-c, and HDL-c decreased significantly in the knockout mice compared with control mice (see figure). However, levels of triglycerides increased significantly.

There was no significant difference in body weight, ratio of liver weight to body weight, or liver cholesterol content between knockout and control mice, and no significant histologic changes were observed in the livers of knockout mice.

The knockout mice had consistent changes in expression of genes that regulate cholesterol metabolism. Expression patterns of Cyp2c54, Abcg5, and Abcg8 were opposite to those observed in mice that expressed the TM6SF2 transgene. CYP2C54 has liver detoxification functions and metabolizes linoleic acid to epoxyoctadecenoic acids.

Levels of alanine aminotransferase were not altered in transgenic or knockout mice.

However, Fan et al found that TM6SF2 promoted cholesterol biosynthesis in a human hepatoma cell line. In the presence of lanosterol and mevalonate, TM6SF2 overexpression increased cholesterol biosynthesis, whereas the E167K mutation reduced this effect.

The authors conclude that TM6SF2 promotes cholesterol biosynthesis, and that the E167K mutation results in partial loss of function. Studies are needed to determine whether TM6SF2 directly converts the substrate zymosterol into 5-α-cholesta-7, 24-dien-3β-ol.

Although TM6SF2 has a limited effect on the expression of genes encoding enzymes involved in cholesterol biosynthesis, its regulation of cholesterol metabolism-related genes and the promotion of cholesterol biosynthesis might cooperate to modulate plasma total cholesterol and LDL-c, and risk for cardiovascular disease and NAFLD.

Further studies of these mice, such as the effects of a long-term high-fat diet, could help determine the effect of TM6SF2 on development of steatohepatitis. The mice could also be placed on methionine, choline, or cholesterol and cholate diets to investigate the direct role of TM6SF2 in liver steatosis, NASH, and fibrosis.

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