Mitochondrial dysfunction-related lipid changes occur in nonalcoholic fatty liver disease progression

Abstract

Nonalcoholic fatty liver disease (NAFLD) comprises fat-accumulating conditions within hepatocytes that can cause severe liver damage and metabolic comorbidities. Studies suggest that mitochondrial dysfunction contributes to its development and progression and that the hepatic lipidome changes extensively in obesity and in NAFLD. To gain insight into the relationship between lipid metabolism and disease progression through different stages of NAFLD, we performed lipidomic analysis of plasma and liver biopsy samples from obese patients with nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH) and from those without NAFLD. Congruent with earlier studies, hepatic lipid levels overall increased with NAFLD. Lipid species that differed with NAFLD severity were related to mitochondrial dysfunction; specifically, hepatic cardiolipin and ubiquinone accumulated in NAFL, and levels of acylcarnitine increased with NASH. We propose that increased levels of cardiolipin and ubiquinone may help to preserve mitochondrial function in early NAFLD, but that mitochondrial function eventually fails with progression to NASH, leading to increased acylcarnitine. We also found a negative association between hepatic odd-chain phosphatidylcholine and NAFLD, which may result from mitochondrial dysfunction-related impairment of branched-chain amino acid catabolism. Overall, these data suggest a close link between accumulation of specific hepatic lipid species, mitochondrial dysfunction, and the progression of NAFLD.

Hepatic Mitochondrial Remodeling is Mechanistically Linked to Insulin Resistance in Nonalcoholic Fatty Liver Disease

“…Acylcarnitines are synthesized by carnitine palmitoyltransferase I (CPTI) to facilitate transport of fatty acids across the inner mitochondrial membrane for subsequent β-oxidation (36). In agreement with evidence from human NASH patients (7, 37), total acylcarnitine content was elevated in OB-CON livers, reflecting an imbalance between CPTI-mediated acylcarnitine production and their disposal via β-oxidation. Rates of complete β-oxidation (acetyl-CoA production) were recently shown to be normal in patients with varying severities of NAFLD (9) and therefore it seems likely that the accumulation of hepatic long-chain acylcarnitines reflects increased mitochondrial fatty acid delivery, rather than impaired oxidation per se .…”

“…Remarkably, all markers of mitochondrial content were reduced in OB-PIO mice (Figure 1A, B). We next measured long-chain acylcarnitine content, as these lipid species are reported to accumulate under conditions of hepatic lipid overload and mitochondrial dysfunction (7, 23). Several acylcarnitine species were increased in OB-CON mice compared to WT, including 18:0-OH, 20:4 and 20:2-OH acylcarnitine, whereas pioglitazone reduced the levels of 20:4, 20:2-OH and 18:1 acylcarnitines (Figure 1C).…”

“…Studies in humans have identified alterations in hepatic mitochondrial metabolism as a central feature of T2D and NAFLD (5, 6), including the remodeling of mitochondrial lipids (7), increases in mitochondrial mass and respiratory capacity (8), altered acetyl-CoA metabolism (9) and excessive tricarboxylic acid (TCA) cycle turnover (5). By driving sustained elevations in oxidative stress, these adaptations are believed to contribute to the inflammatory, fibrotic milieu associated with disease progression (8) and warrant the development of therapies specifically targeting hepatic mitochondrial metabolism.…”

Lipotoxicity plays a key role in the development of both insulin resistance and muscle atrophy in patients with type 2 diabetes

“…It is likely that in individuals with obesity, enlarged adipose tissue depots as well as insulin resistance of the adipose tissue contribute to fat disposition in the liver, thereby providing a link between obesity, insulin resistance, and liver steatosis. The liver on its turn also secretes a wide range of lipids, including high levels of triacylglycerols via the secretion of very‐low‐density lipoproteins . These lipids can accumulate in skeletal muscle and contribute to the development of insulin resistance (see following paragraph).…”

“…The liver on its turn also secretes a wide range of lipids, including high levels of triacylglycerols via the secretion of very-low-density lipoproteins. 73 These lipids can accumulate in skeletal muscle and contribute to the development of insulin resistance (see following paragraph). In addition, lipids secreted by the liver can also play an important role in the development of atherosclerosis and increase the risk for cardiovascular problems and other complications such as nephropathy, retinopathy, and neuropathy.…”